Human TARPP genes and polypeptides

ABSTRACT

The present invention relates to all facets of novel polynucleotides, the polypeptides they encode, antibodies and specific binding partners thereto, and their applications to research, diagnosis, drug discovery, therapy, clinical medicine, forensic science and medicine, etc. The polynucleotides are highly in brain, pituitary, muscle, and thymus, and are therefore useful in variety of ways, including, but not limited to, as molecular markers, as drug targets, and for detecting, diagnosing, staging, monitoring, prognosticating, preventing or treating, determining predisposition to, etc., diseases and conditions, relating to such tissues. The genes and polypeptides can also be used as markers for immature T-cells.

DESCRIPTION OF THE DRAWINGS

[0001]FIG. 1 is the amino acid aligmnents of the different splicevariants of human TARPP, Br137A (SEQ ID NO 4), B (SEQ ID NO 6), C (SEQID NO 8), D (SEQ ID NO 10; SEQ ID NO 13, NM_(—)016300), and E (SEQ ID NO2), and partial clone AL133109 (SEQ ID NO 13).

[0002]FIG. 2 is a schematic drawing showing the differences between thevarious forms of human TARPP.

[0003]FIG. 3 shows amino acid alignments of the different splicevariants of human TARPP (Br137A, B, C, D, and E) with mouse TARPP(NM_(—)033264; SEQ ID NO 11).

DESCRIPTION OF THE INVENTION

[0004] The present invention relates to all facets of human TARPP (alsoknown as human Br137), polypeptides encoded by it, antibodies andspecific binding partners thereto, and their applications to research,diagnosis, drug discovery, therapy, clinical medicine, forensic scienceand medicine, etc. Human TARPP polynucleotides, polypeptides,antibodies, etc., are useful in variety of ways, including, but notlimited to, as a molecular markers, as drug targets, and for detecting,diagnosing, staging, monitoring, prognosticating, preventing ortreating, determining predisposition to, etc., diseases and conditionsrelating to T-cells and dopaminergic pathways. The identification ofspecific genes, and groups of genes, expressed in pathwaysphysiologically relevant to these conditions permits the definition offunctional and disease pathways, and the delineation of targets in thesepathways which are useful in diagnostic, therapeutic, and clinicalapplications. The present invention also relates to methods of using thepolynucleotides and related products (proteins, antibodies, etc.) inbusiness and computer-related methods, e.g., advertising, displaying,offering, selling, etc., such products for sale, commercial use,licensing, etc.

[0005] Human TARPP (thymocyte cyclic AMP regulated phosphoprotein, or,Br 137A, B, C, D, and E) is represented by a family of alternativesplice variants. FIGS. 1 and 2 summarize the differences between themultiple forms. Br137E is an 847 amino acid polypeptide. Its nucleotideand amino acid sequences are shown in SEQ ID NOS 1 and 2. Br137B (SEQ IDNO 5 and 6) has a deletion of amino acids 267-300, Br137A (SEQ ID NO 3and 4) has a deletion of amino acids 312-331, and Br137C (SEQ ID NO 7and 8) has a deletion of both these domains. Br137D contains only thefirst 87 amino acids followed by a two-amino acid N-terminus whichdiffers from the other forms. A partial clone, AL133109 as shown in FIG.1, is missing the first 161 amino acids of Br137E, as well as having anamino acid difference at position 312 (SEQ ID NO 2).

[0006] Br137E contains a nuclear localization signal at about aminoacids 107-124, an R3H domain (single-stranded nucleic acid bindingdomain) at about amino acids 147-224, and a proline rich region at aboutamino acids 476-682. These domains are also present in the A-C spliceforms, but at different amino acid positions. Human TARPP has nucleicacid binding activity conferred by the corresponding binding domainindicating that it can bind nucleic acids, preferably single-strandedDNA or RNA. This binding activity can be assayed routinely, e.g., usinggel electrophoresis band shift assays, e.g., as carried out in, e.g.,U.S. Pat. Nos. 6,333,407 and 5,789,538, ELISA-based assays (e.g.,Mercury™ TransFactor Kit from Clontech), and other assays which detectDNA-protein interactions.

[0007] The Br137 family represent the human homologs of murine TARPP(thymocyte ARPP) (M_(—)033264; SEQ ID NO 11; “Mouse” in FIG. 3). Br137Ehas about 83% amino acid identity and 87% homology with it (calculatedusing the BLAST algorithm). See, FIG. 3 (NM_(—)033264 is murine TARPP).In addition to amino acid sequence differences between the two proteins,human TARPP has an insertion at about amino acid positions 549-572 ofSEQ ID NO 2 which is not present in the mouse protein. See, FIG. 3.

[0008] Originally, a 21 kDa polypeptide was isolated from rat basalganglia based on its phosphorylation by cAMP-dependent protein kinase(PKA). Williams et al., J. Neurosci., 9:3631-3637, 1989. It was namedARPP-21 (cAMP-regulated phosphoprotein). Activation of dopaminereceptors resulted in an increase in the phosphorylation of ARPP-21.Caporaso et al., Neuropharm., 39:1637-1644, 2000. Human ARPP-21 (Br137D)contains 89 amino acids (NM_(—)016300; SEQ ID NO 13).

[0009] A high molecular weight polypeptide of ARPP-21 was subsequentlyidentified in T-cells and named TARPP. Kisielow et al., Eur. J.Immunol., 31:1141-1149, 2001. This polypeptide contains ARPP-21 sequenceat its 5′ end, but a novel 3′ end coding for more than 700 additionalamino acids (for a total of 807 amino acids). Murine TARPP appears to beinvolved in the regulation of thymocyte maturation and TCRrearrangement. Expression of TARPP is down-regulated after the TCRsignals delivered. It is highly expressed in immature thymocytes and isassociated with the commitment to the T-cell lineage, making it highlyselective marker for T-cell commitment. See, Kisielow, ibid. Aftercommitment to the T-cell lineage during positive selection, itsexpression is turned off.

[0010] There appear to be several members of the human TARPP family.KIAA0029 is a hypothetical protein that shares about 45% amino acidsequence identity and 59% homology with Br137E. KIAA1002, a secondhypothetical protein, has about 42% amino acid identity and 54% homologyto it.

[0011] Human TARPP is highly expressed in brain, pituitary, muscle, andthymus. It is expressed at lower levels in adrenal gland, bone marrow,heart, small intestine, kidney, liver, ovary, prostate, stomach, testis,and thyroid. There was virtually no detectable expression in colon,lung, lymph node, peripheral lymphocytes, mammary gland, pancreas, anduterus.

[0012] As indicated by its expression pattern, human TARPP is involvedthe maturation of T-cells, especially in the rearrangement of the TCR.For this reason, it can be used to modulate T-cells, e.g., in allergy,auto immune disease (e.g., rheumatoid arthritis and multiple sclerosis),and graft-host disease. It can also be used a marker to determine theindex of mature versus immature T-cells, where human TARPP is marker ofimmature T-cells. Additionally, human TARPP is phosphorylated upondopamine receptor activation, indicating an involvement in dopaminepathways. Consequently, it is target for diseases that involve dopamine,including, e.g., schizophrenia, substance abuse and addiction, anxiety,Parkinson's disease, and other dopaminergic diseases and conditions.

[0013] Human TARPP is localized to chromosomal band 3p21.33. There areseveral disorders genetically mapped to this region, including, e.g.,retinal vasculopathy with cerebral leukodystrophy (OMIM 192315),deafness, neurosensory, autosomal recessive 6 (OMIM 600971), and lungcancer. Nucleic acids of the present invention can be used as linkagemarkers, diagnostic targets, therapeutic targets, for any of thementioned disorders, as well as any disorders or genes mapping inproximity to it.

[0014] Nucleic Acids

[0015] A mammalian polynucleotide, or fragment thereof, of the presentinvention is a polynucleotide having a nucleotide sequence obtainablefrom a natural source. It therefore includes naturally-occurring normal,naturally-occurring mutant, and naturally-occurring polymorphic alleles(e.g., SNPs), differentially-spliced transcripts, splice-variants, etc.By the term “naturally-occurring,” it is meant that the polynucleotideis obtainable from a natural source, e.g., animal tissue and cells, bodyfluids, tissue culture cells, forensic samples. Natural sources include,e.g., living cells obtained from tissues and whole organisms, tumors,cultured cell lines, including primary and immortalized cell lines.Naturally-occurring mutations can include deletions (e.g., a truncatedamino- or carboxy-terminus), substitutions, inversions, or additions ofnucleotide sequence. These genes can be detected and isolated bypolynucleotide hybridization according to methods which one skilled inthe art would know, e.g., as discussed below.

[0016] A polynucleotide according to the present invention can beobtained from a variety of different sources. It can be obtained fromDNA or RNA, such as polyadenylated mRNA or total RNA, e.g., isolatedfrom tissues, cells, or whole organism. The polynucleotide can beobtained directly from DNA or RNA, from a cDNA library, from a genomiclibrary, etc. The polynucleotide can be obtained from a cell or tissue(e.g., from an embryonic or adult tissues) at a particular stage ofdevelopment, having a desired genotype, phenotype, disease status, etc.A polynucleotide which “codes without interruption” refers to apolynucleotide having a continuous open reading frame (“ORF”) ascompared to an ORF which is interrupted by introns or other noncodingsequences.

[0017] Polynucleotides and polypeptides (including any part of humanTARPP) can be excluded as compositions from the present invention if,e.g., listed in a publicly available databases on the day thisapplication was filed and/or disclosed in a patent application having anearlier filing or priority date than this application and/or conceivedand/or reduced to practice earlier than a polynucleotide in thisapplication.

[0018] As described herein, the phrase “an isolated polynucleotide whichis SEQ ID NO,” or “an isolated polynucleotide which is selected from SEQID NO,” refers to an isolated nucleic acid molecule from which therecited sequence was derived (e.g., a cDNA derived from mRNA; cDNAderived from genomic DNA). Because of sequencing errors, typographicalerrors, etc., the actual naturally-occurring sequence may differ from aSEQ ID listed herein. Thus, the phrase indicates the specific moleculefrom which the sequence was derived, rather than a molecule having thatexact recited nucleotide sequence, analogously to how a culturedepository number refers to a specific cloned fragment in a cryotube.

[0019] As explained in more detail below, a polynucleotide sequence ofthe invention can contain the complete sequence as shown in SEQ ID NO 1,3, 5, 7, 9, and others, degenerate sequences thereof, anti-sense,muteins thereof, genes comprising said sequences, full-length cDNAscomprising said sequences, complete genomic sequences, fragmentsthereof, homologs, primers, nucleic acid molecules which hybridizethereto, derivatives thereof, etc.

[0020] Genomic

[0021] The present invention also relates genomic DNA from which thepolynucleotides of the present invention can be derived. A genomic DNAcoding for a human, mouse, or other mammalian polynucleotide, can beobtained routinely, for example, by screening a genomic library (e.g., aYAC library) with a polynucleotide of the present invention, or bysearching nucleotide databases, such as GenBank and EMBL, for matches.Promoter and other regulatory regions (including both 5′ and 3′ regions)can be identified upstream or downstream of coding and expressed RNAs,and assayed routinely for activity, e.g., by joining to a reporter gene(e.g., CAT, GFP, alkaline phosphatase, luciferase, galatosidase). Apromoter obtained from a gene can be used, e.g., in gene therapy toobtain tissue-specific expression of a heterologous gene (e.g., codingfor a therapeutic product or cytotoxin). 3′-untranslated sequences (aswell as introns) can be used, e.g., to stabilize transcripts, to targettranscripts, etc.

[0022] Constructs

[0023] A polynucleotide of the present invention can comprise additionalpolynucleotide sequences, e.g., sequences to enhance expression,detection, uptake, cataloging, tagging, etc. A polynucleotide caninclude only coding sequence; a coding sequence and additionalnon-naturally occurring or heterologous coding sequence (e.g., sequencescoding for leader, signal, secretory, targeting, enzymatic, fluorescent,antibiotic resistance, and other functional or diagnostic peptides);coding sequences and non-coding sequences, e.g., untranslated sequencesat either a 5′ or 3′ end, or dispersed in the coding sequence, e.g.,introns.

[0024] A polynucleotide according to the present invention also cancomprise an expression control sequence operably linked to apolynucleotide as described above. The phrase “expression controlsequence” means a polynucleotide sequence that regulates expression of apolypeptide coded for by a polynucleotide to which it is functionally(“operably”) linked. Expression can be regulated at the level of themRNA or polypeptide. Thus, the expression control sequence includesmRNA-related elements and protein-related elements. Such elementsinclude promoters, enhancers (viral or cellular), ribosome bindingsequences, transcriptional terminators, etc. An expression controlsequence is operably linked to a nucleotide coding sequence when theexpression control sequence is positioned in such a manner to effect orachieve expression of the coding sequence. For example, when a promoteris operably linked 5′ to a coding sequence, expression of the codingsequence is driven by the promoter. Expression control sequences caninclude an initiation codon and additional nucleotides to place apartial nucleotide sequence of the present invention in-frame in orderto produce a polypeptide (e.g., pET vectors from Promega have beendesigned to permit a molecule to be inserted into all three readingframes to identify the one that results in polypeptide expression).Expression control sequences can be heterologous or endogenous to thenormal gene.

[0025] A polynucleotide of the present invention can also comprisenucleic acid vector sequences, e.g., for cloning, expression,amplification, selection, etc. Any effective vector can be used. Avector is, e.g., a polynucleotide molecule which can replicateautonomously in a host cell, e.g., containing an origin of replication.Vectors can be useful to perform manipulations, to propagate, and/orobtain large quantities of the recombinant molecule in a desired host. Askilled worker can select a vector depending on the purpose desired,e.g., to propagate the recombinant molecule in bacteria, yeast, insect,or mammalian cells. The following vectors are provided by way ofexample. Bacterial: pQE70, pQE60, pQE-9 (Qiagen), pBS, pD10,Phagescript, phiX174, pBK Phagemid, pNH8A, pNH16a, pNH18Z, pNH46A(Stratagene); Bluescript KS+II (Stratagene); ptrc99a, pKK223-3,pKK233-3, pDR540, pRIT5 (Pharmacia). Eukaryotic: PWLNEO, pSV2CAT, pOG44,pXT1, pSG (Stratagene), pSVK3, PBPV, PMSG, pSVL (Pharmacia),pCR2.1/TOPO, pCRII/TOPO, pCR4/TOPO, pTrcHisB, pCMV6-XL4, etc. However,any other vector, e.g., plasmids, viruses, or parts thereof, may be usedas long as they are replicable and viable in the desired host. Thevector can also comprise sequences which enable it to replicate in thehost whose genome is to be modified.

[0026] Hybridization

[0027] Polynucleotide hybridization, as discussed in more detail below,is useful in a variety of applications, including, in gene detectionmethods, for identifying mutations, for making mutations, to identifyhomologs in the same and different species, to identify related membersof the same gene family, in diagnostic and prognostic assays, intherapeutic applications (e.g., where an antisense polynucleotide isused to inhibit expression), etc.

[0028] The ability of two single-stranded polynucleotide preparations tohybridize together is a measure of their nucleotide sequencecomplementarity, e.g., base-pairing between nucleotides, such as A-T,G-C, etc. The invention thus also relates to polynucleotides, and theircomplements, which hybridize to a polynucleotide comprising a nucleotidesequence as set forth in SEQ ID NO 1, 3, 5, 7, 9, and others and genomicsequences thereof. A nucleotide sequence hybridizing to the lattersequence will have a complementary polynucleotide strand, or act as atemplate for one in the presence of a polymerase (i.e., an appropriatepolynucleotide synthesizing enzyme). The present invention includes bothstrands of polynucleotide, e.g., a sense strand and an anti-sensestrand.

[0029] Hybridization conditions can be chosen to select polynucleotideswhich have a desired amount of nucleotide complementarity with thenucleotide sequences set forth in SEQ ID NO 1, 3, 5, 7, 9, and othersand genomic sequences thereof. A polynucleotide capable of hybridizingto such sequence, preferably, possesses, e.g., about 70%, 75%, 80%, 85%,87%, 90%, 92%, 95%, 97%, 99%, or 100% complementarity, between thesequences. The present invention particularly relates to polynucleotidesequences which hybridize to the nucleotide sequences set forth in SEQID NO 1, 3, 5, 7, 9, and others or genomic sequences thereof, under lowor high stringency conditions. These conditions can be used, e.g., toselect corresponding homologs in non-human species.

[0030] Polynucleotides which hybridize to polynucleotides of the presentinvention can be selected in various ways. Filter-type blots (i.e.,matrices containing polynucleotide, such as nitrocellulose), glasschips, and other matrices and substrates comprising polynucleotides(short or long) of interest, can be incubated in a prehybridizationsolution (e.g., 6×SSC, 0.5% SDS, 100 μg/ml denatured salmon sperm DNA,5× Denhardt's solution, and 50% formamide), at 22-68° C., overnight, andthen hybridized with a detectable polynucleotide probe under conditionsappropriate to achieve the desired stringency. In general, when highhomology or sequence identity is desired, a high temperature can be used(e.g., 65° C.). As the homology drops, lower washing temperatures areused. For salt concentrations, the lower the salt concentration, thehigher the stringency. The length of the probe is another consideration.Very short probes (e.g., less than 100 base pairs) are washed at lowertemperatures, even if the homology is high. With short probes, formamidecan be omitted. See, e.g., Current Protocols in Molecular Biology,Chapter 6, Screening of Recombinant Libraries; Sambrook et al.,Molecular Cloning, 1989, Chapter 9.

[0031] For instance, high stringency conditions can be achieved byincubating the blot overnight (e.g., at least 12 hours) with a longpolynucleotide probe in a hybridization solution containing, e.g., about5×SSC, 0.5% SDS, 100 μg/ml denatured salmon sperm DNA and 50% formamide,at 42° C. Blots can be washed at high stringency conditions that allow,e.g., for less than 5% bp mismatch (e.g., wash twice in 0.1% SSC and0.1% SDS for 30 min at 65° C.), i.e., selecting sequences having 95% orgreater sequence identity.

[0032] Other non-limiting examples of high stringency conditionsincludes a final wash at 65° C. in aqueous buffer containing 30 mM NaCland 0.5% SDS. Another example of high stringent conditions ishybridization in 7% SDS, 0.5 M NaPO₄, pH 7, 1 mM EDTA at 50° C., e.g.,overnight, followed by one or more washes with a 1% SDS solution at 42°C. Whereas high stringency washes can allow for less than 5% mismatch,reduced or low stringency conditions can permit up to 20% nucleotidemismatch. Hybridization at low stringency can be accomplished as above,but using lower formamide conditions, lower temperatures and/or lowersalt concentrations, as well as longer periods of incubation time.

[0033] Hybridization can also be based on a calculation of meltingtemperature (Tm) of the hybrid formed between the probe and its target,as described in Sambrook et al.. Generally, the temperature Tm at whicha short oligonucleotide (containing 18 nucleotides or fewer) will meltfrom its target sequence is given by the following equation: Tm=(numberof A's and T's)×2° C.+(number of C's and G's)×4° C. For longermolecules, Tm=81.5+16.6 log₁₀[Na⁺]+0.41(% GC)−600/N where [Na⁺] is themolar concentration of sodium ions, % GC is the percentage of GC basepairs in the probe, and N is the length. Hybridization can be carriedout at several degrees below this temperature to ensure that the probeand target can hybridize. Mismatches can be allowed for by lowering thetemperature even further.

[0034] Stringent conditions can be selected to isolate sequences, andtheir complements, which have, e.g., at least about 90%, 95%, or 97%,nucleotide complementarity between the probe (e.g., a shortpolynucleotide of SEQ ID NO 1, 3, 5, 7, 9, and others or genomicsequences thereof) and a target polynucleotide.

[0035] Other homologs of polynucleotides of the present invention can beobtained from mammalian and non-mammalian sources according to variousmethods. For example, hybridization with a polynucleotide can beemployed to select homologs, e.g., as described in Sambrook et al.,Molecular Cloning, Chapter 11, 1989. Such homologs can have varyingamounts of nucleotide and amino acid sequence identity and similarity tosuch polynucleotides of the present invention. Mammalian organismsinclude, e.g., mice, rats, monkeys, pigs, cows, etc. Non-mammalianorganisms include, e.g., vertebrates, invertebrates, zebra fish,chicken, Drosophila, C. elegans, Xenopus, yeast such as S. pombe, S.cerevisiae, roundworms, prokaryotes, plants, Arabidopsis, artemia,viruses, etc. The degree of nucleotide sequence identity between humanand mouse can be about, e.g. 70% or more, 85% or more for open readingframes, etc.

[0036] Alignment

[0037] Alignments can be accomplished by using any effective algorithm.For pairwise alignments of DNA sequences, the methods described byWilbur-Lipman (e.g., Wilbur and Lipman, Proc. Natl. Acad. Sci.,80:726-730, 1983) or Martinez/Needleman-Wunsch (e.g., Martinez, NucleicAcid Res., 11:4629-4634, 1983) can be used. For instance, if theMartinez/Needleman-Wunsch DNA alignment is applied, the minimum matchcan be set at 9, gap penalty at 1.10, and gap length penalty at 0.33.The results can be calculated as a similarity index, equal to the sum ofthe matching residues divided by the sum of all residues and gapcharacters, and then multiplied by 100 to express as a percent.Similarity index for related genes at the nucleotide level in accordancewith the present invention can be greater than 70%, 80%, 85%, 90%, 95%,99%, or more. Pairs of protein sequences can be aligned by theLipman-Pearson method (e.g., Lipman and Pearson, Science, 227:1435-1441,1985) with k-tuple set at 2, gap penalty set at 4, and gap lengthpenalty set at 12. Results can be expressed as percent similarity index,where related genes at the amino acid level in accordance with thepresent invention can be greater than 65%, 70%, 75%, 80%, 85%, 90%, 95%,99%, or more. Various commercial and free sources of alignment programsare available, e.g., MegAlign by DNA Star, BLAST (National Center forBiotechnology Information), BCM (Baylor College of Medicine) Launcher,etc. BLAST can be used to calculate amino acid sequence identity, aminoacid sequence homology, and nucleotide sequence identity.

[0038] Percent sequence identity can also be determined by otherconventional methods, e.g., as described in Altschul et al., Bull. Math.Bio. 48: 603-616, 1986 and Henikoff and Henikoff, Proc. Natl. Acad. Sci.USA 89:10915-10919, 1992.

[0039] Specific Polynucleotide Probes

[0040] A polynucleotide of the present invention can comprise anycontinuous nucleotide sequence of SEQ ID NO 1, 3, 5, 7, 9, and others,sequences which share sequence identity thereto, or complements thereof.The term “probe” refers to any substance that can be used to detect,identify, isolate, etc., another substance. A polynucleotide probe iscomprised of nucleic acid can be used to detect, identify, etc., othernucleic acids, such as DNA and RNA.

[0041] These polynucleotides can be of any desired size that iseffective to achieve the specificity desired. For example, a probe canbe from about 7 or 8 nucleotides to several thousand nucleotides,depending upon its use and purpose. For instance, a probe used as aprimer PCR can be shorter than a probe used in an ordered array ofpolynucleotide probes. Probe sizes vary, and the invention is notlimited in any way by their size, e.g., probes can be from about 7-2000nucleotides, 7-1000, 8-700, 8-600, 8-500, 8-400, 8-300, 8-150, 8-100,8-75, 7-50, 10-25, 14-16, at least about 8, at least about 10, at leastabout 15, at least about 25, etc. The polynucleotides can havenon-naturally-occurring nucleotides, e.g., inosine, AZT, 3TC, etc. Thepolynucleotides can have 100% sequence identity or complementarity to asequence of SEQ ID NO 1, 3, 5, 7, 9, and others, or it can havemismatches or nucleotide substitutions, e.g., 1, 2, 3, 4, or 5substitutions. The probes can be single-stranded or double-stranded.

[0042] In accordance with the present invention, a polynucleotide can bepresent in a kit, where the kit includes, e.g., one or morepolynucleotides, a desired buffer (e.g., phosphate, tris, etc.),detection compositions, RNA or cDNA from different tissues to be used ascontrols, libraries, etc. The polynucleotide can be labeled orunlabeled, with radioactive or non-radioactive labels as known in theart. Kits can comprise one or more pairs of polynucleotides foramplifying nucleic acids specific for human TARPP, e.g., comprising aforward and reverse primer effective in PCR. These include both senseand anti-sense orientations. For instance, in PCR-based methods (such asRT-PCR), a pair of primers are typically used, one having a sensesequence and the other having an antisense sequence.

[0043] Another aspect of the present invention is a nucleotide sequencethat is specific to, or for, a selective polynucleotide. The phrases“specific for” or “specific to” a polynucleotide have a functionalmeaning that the polynucleotide can be used to identify the presence ofone or more target genes in a sample. It is specific in the sense thatit can be used to detect polynucleotides above background noise(“non-specific binding”). A specific sequence is a defined order ofnucleotides which occurs in the polynucleotide, e.g., in the nucleotidesequences of SEQ ID NO 1, 3, 5, 7, 9, and others. A probe or mixture ofprobes can comprise a sequence or sequences that are specific to aplurality of target sequences, e.g., where the sequence is a consensussequence, a functional domain, etc., e.g., capable of recognizing afamily of related genes. Such sequences can be used as probes in any ofthe methods described herein or incorporated by reference. Both senseand antisense nucleotide sequences are included. A specificpolynucleotide according to the present invention can be determinedroutinely.

[0044] A polynucleotide comprising a specific sequence can be used as ahybridization probe to identify the presence of, e.g., human or mousepolynucleotide, in a sample comprising a mixture of polynucleotides,e.g., on a Northern blot. Hybridization can be performed under highstringent conditions (see, above) to select polynucleotides (and theircomplements which can contain the coding sequence) having at least 90%,95%, 99%, etc., identity (i.e., complementarity) to the probe, but lessstringent conditions can also be used. A specific polynucleotidesequence can also be fused in-frame, at either its 5′ or 3′ end, tovarious nucleotide sequences as mentioned throughout the patent,including coding sequences for enzymes, detectable markers, GFP, etc,expression control sequences, etc.

[0045] A polynucleotide probe, especially one that is specific to apolynucleotide of the present invention, can be used in gene detectionand hybridization methods as already described. In one embodiment, aspecific polynucleotide probe can be used to detect whether a particulartissue or cell-type is present in a target sample. To carry out such amethod, a selective polynucleotide can be chosen which is characteristicof the desired target tissue. Such polynucleotide is preferably chosenso that it is expressed or displayed in the target tissue, but not inother tissues which are present in the sample. Starting from theselective polynucleotide, a specific polynucleotide probe can bedesigned which hybridizes (if hybridization is the basis of the assay)under the hybridization conditions to the selective polynucleotide,whereby the presence of the selective polynucleotide can be determined.

[0046] Probes which are specific for polynucleotides of the presentinvention can also be prepared using involve transcription-basedsystems, e.g., incorporating an RNA polymerase promoter into a selectivepolynucleotide of the present invention, and then transcribinganti-sense RNA using the polynucleotide as a template. See, e.g., U.S.Pat. No. 5,545,522.

[0047] Polynucleotide Composition

[0048] A polynucleotide according to the present invention can comprise,e.g., DNA, RNA, synthetic polynucleotide, peptide polynucleotide,modified nucleotides, dsDNA, ssDNA, ssRNA, dsRNA, and mixtures thereof.A polynucleotide can be single- or double-stranded, triplex, DNA:RNA,duplexes, comprise hairpins, and other secondary structures, etc.Nucleotides comprising a polynucleotide can be joined via various knownlinkages, e.g., ester, sulfamate, sulfamide, phosphorothioate,phosphoramidate, methylphosphonate, carbamate, etc., depending on thedesired purpose, e.g., resistance to nucleases, such as RNAse H,improved in vivo stability, etc. See, e.g., U.S. Pat. No. 5,378,825. Anydesired nucleotide or nucleotide analog can be incorporated, e.g.,6-mercaptoguanine, 8-oxo-guanine, etc.

[0049] Various modifications can be made to the polynucleotides, such asattaching detectable markers (avidin, biotin, radioactive elements,fluorescent tags and dyes, energy transfer labels, energy-emittinglabels, binding partners, etc.) or moieties which improve hybridization,detection, and/or stability. The polynucleotides can also be attached tosolid supports, e.g., nitrocellulose, magnetic or paramagneticmicrospheres (e.g., as described in U.S. Pat. Nos. 5,411,863; 5,543,289;for instance, comprising ferromagnetic, supermagnetic, paramagnetic,superparamagnetic, iron oxide and polysaccharide), nylon, agarose,diazotized cellulose, latex solid microspheres, polyacrylamides, etc.,according to a desired method. See, e.g., U.S. Pat. Nos. 5,470,967,5,476,925, and 5,478,893.

[0050] Polynucleotide according to the present invention can be labeledaccording to any desired method. The polynucleotide can be labeled usingradioactive tracers such as ³²P, ³⁵S, ³H, or ¹⁴C, to mention somecommonly used tracers. The radioactive labeling can be carried outaccording to any method, such as, for example, terminal labeling at the3′ or 5′ end using a radiolabeled nucleotide, polynucleotide kinase(with or without dephosphorylation with a phosphatase) or a ligase(depending on the end to be labeled). A non-radioactive labeling canalso be used, combining a polynucleotide of the present invention withresidues having immunological properties (antigens, haptens), a specificaffinity for certain reagents (ligands), properties enabling detectableenzyme reactions to be completed (enzymes or coenzymes, enzymesubstrates, or other substances involved in an enzymatic reaction), orcharacteristic physical properties, such as fluorescence or the emissionor absorption of light at a desired wavelength, etc.

[0051] Nucleic Acid Detection Methods

[0052] Another aspect of the present invention relates to methods andprocesses for detecting human TARPP. Detection methods have a variety ofapplications, including for diagnostic, prognostic, forensic, andresearch applications. To accomplish gene detection, a polynucleotide inaccordance with the present invention can be used as a “probe.” The term“probe” or “polynucleotide probe” has its customary meaning in the art,e.g., a polynucleotide which is effective to identify (e.g., byhybridization), when used in an appropriate process, the presence of atarget polynucleotide to which it is designed. Identification caninvolve simply determining presence or absence, or it can bequantitative, e.g., in assessing amounts of a gene or gene transcriptpresent in a sample. Probes can be useful in a variety of ways, such asfor diagnostic purposes, to identify homologs, and to detect,quantitate, or isolate a polynucleotide of the present invention in atest sample.

[0053] Assays can be utilized which permit quantification and/orpresence/absence detection of a target nucleic acid in a sample. Assayscan be performed at the single-cell level, or in a sample comprisingmany cells, where the assay is “averaging” expression over the entirecollection of cells and tissue present in the sample. Any suitable assayformat can be used, including, but not limited to, e.g., Southern blotanalysis, Northern blot analysis, polymerase chain reaction (“PCR”)(e.g., Saiki et al., Science, 241:53, 1988; U.S. Pat. Nos. 4,683,195,4,683,202, and 6,040,166; PCR Protocols: A Guide to Methods andApplications, Innis et al., eds., Academic Press, New York, 1990),reverse transcriptase polymerase chain reaction (“RT-PCR”), anchoredPCR, rapid amplification of cDNA ends (“RACE”) (e.g., Schaefer in GeneCloning and Analysis: Current Innovations, Pages 99-115, 1997), ligasechain reaction (“LCR”) (EP 320 308), one-sided PCR (Ohara et al., Proc.Natl. Acad. Sci., 86:5673-5677, 1989), indexing methods (e.g., U.S. Pat.No. 5,508,169), in situ hybridization, differential display (e.g., Lianget al., Nucl. Acid. Res., 21:3269-3275, 1993; U.S. Pat. Nos. 5,262,311,5,599,672 and 5,965,409; WO97/18454; Prashar and Weissman, Proc. Natl.Acad. Sci., 93:659-663, and U.S. Pat. Nos. 6,010,850 and 5,712,126;Welsh et al., Nucleic Acid Res., 20:4965-4970, 1992, and U.S. Pat. No.5,487,985) and other RNA fingerprinting techniques, nucleic acidsequence based amplification (“NASBA”) and other transcription basedamplification systems (e.g., U.S. Pat. Nos. 5,409,818 and 5,554,527; WO88/10315), polynucleotide arrays (e.g., U.S. Pat. Nos. 5,143,854,5,424,186; 5,700,637, 5,874,219, and 6,054,270; PCT WO 92/10092; PCT WO90/15070), Qbeta Replicase (PCT/US87/00880), Strand DisplacementAmplification (“SDA”), Repair Chain Reaction (“RCR”), nucleaseprotection assays, subtraction-based methods, Rapid-Scan™, etc.Additional useful methods include, but are not limited to, e.g.,template-based amplification methods, competitive PCR (e.g., U.S. Pat.No. 5,747,251), redox-based assays (e.g., U.S. Pat. No. 5,871,918),Taqman-based assays (e.g., Holland et al., Proc. Natl. Acad, Sci.,88:7276-7280, 1991; U.S. Pat. Nos. 5,210,015 and 5,994,063), real-timefluorescence-based monitoring (e.g., U.S. Pat. No. 5,928,907), molecularenergy transfer labels (e.g., U.S. Pat. Nos. 5,348,853, 5,532,129,5,565,322, 6,030,787, and 6,117,635; Tyagi and Kramer, Nature Biotech.,14:303-309, 1996). Any method suitable for single cell analysis of geneor protein expression can be used, including in situ hybridization,immunocytochemistry, MACS, FACS, flow cytometry, etc. For single cellassays, expression products can be measured using antibodies, PCR, orother types of nucleic acid amplification (e.g., Brady et al., MethodsMol. & Cell. Biol. 2, 17-25, 1990; Eberwine et al., 1992, Proc. Natl.Acad. Sci., 89, 3010-3014, 1992; U.S. Pat. No. 5,723,290). These andother methods can be carried out conventionally, e.g., as described inthe mentioned publications.

[0054] Many of such methods may require that the polynucleotide islabeled, or comprises a particular nucleotide type useful for detection.The present invention includes such modified polynucleotides that arenecessary to carry out such methods. Thus, polynucleotides can be DNA,RNA, DNA: RNA hybrids, PNA, etc., and can comprise any modification orsubstituent which is effective to achieve detection.

[0055] Detection can be desirable for a variety of different purposes,including research, diagnostic, prognostic, and forensic. For diagnosticpurposes, it may be desirable to identify the presence or quantity of apolynucleotide sequence in a sample, where the sample is obtained fromtissue, cells, body fluids, etc. In a preferred method as described inmore detail below, the present invention relates to a method ofdetecting a polynucleotide comprising, contacting a targetpolynucleotide in a test sample with a polynucleotide probe underconditions effective to achieve hybridization between the target andprobe; and detecting hybridization.

[0056] Any test sample in which it is desired to identify apolynucleotide or polypeptide thereof can be used, including, e.g.,blood, urine, saliva, stool (for extracting nucleic acid, see, e.g.,U.S. Pat. No. 6,177,251), swabs comprising tissue, biopsied tissue,tissue sections, cultured cells, etc.

[0057] Detection can be accomplished in combination with polynucleotideprobes for other genes, e.g., genes which are expressed in other diseasestates, tissues, cells, such as brain, heart, kidney, spleen, thymus,liver, stomach, small intestine, colon, muscle, lung, testis, placenta,pituitary, thyroid, skin, adrenal gland, pancreas, salivary gland,uterus, ovary, prostate gland, peripheral blood cells (T-cells,lymphocytes, etc.), embryo, normal breast fat, adult and embryonic stemcells, specific cell-types, such as endothelial, epithelial, myocytes,adipose, luminal epithelial, basoepithelial, myoepithelial, stromalcells, etc.

[0058] Polynucleotides can be used in wide range of methods andcompositions, including for detecting, diagnosing, staging, grading,assessing, prognosticating, etc. diseases and disorders associated withhuman TARPP, for monitoring or assessing therapeutic and/or preventativemeasures, in ordered arrays, etc. Any method of detecting genes andpolynucleotides of SEQ ID NO 1, 3, 5, 7, 9, and others can be used;certainly, the present invention is not to be limited how such methodsare implemented.

[0059] Along these lines, the present invention relates to methods ofdetecting human TARPP in a sample comprising nucleic acid. Such methodscan comprise one or more the following steps in any effective order,e.g., contacting said sample with a polynucleotide probe underconditions effective for said probe to hybridize specifically to nucleicacid in said sample, and detecting the presence or absence of probehybridized to nucleic acid in said sample, wherein said probe is apolynucleotide which is SEQ ID NO 1, 3, 5, 7, 9, and others, apolynucleotide having, e.g., about 70%, 80%, 85%, 90%, 95%, 99%, or moresequence identity thereto, effective or specific fragments thereof, orcomplements thereto. The detection method can be applied to any sample,e.g., cultured primary, secondary, or established cell lines, tissuebiopsy, blood, urine, stool, cerebral spinal fluid, and other bodilyfluids, for any purpose.

[0060] Contacting the sample with probe can be carried out by anyeffective means in any effective environment. It can be accomplished ina solid, liquid, frozen, gaseous, amorphous, solidified, coagulated,colloid, etc., mixtures thereof, matrix. For instance, a probe in anaqueous medium can be contacted with a sample which is also in anaqueous medium, or which is affixed to a solid matrix, or vice-versa.

[0061] Generally, as used throughout the specification, the term“effective conditions” means, e.g., the particular milieu in which thedesired effect is achieved. Such a milieu, includes, e.g., appropriatebuffers, oxidizing agents, reducing agents, pH, co-factors, temperature,ion concentrations, suitable age and/or stage of cell (such as, inparticular part of the cell cycle, or at a particular stage whereparticular genes are being expressed) where cells are being used,culture conditions (including substrate, oxygen, carbon dioxide, etc.).When hybridization is the chosen means of achieving detection, the probeand sample can be combined such that the resulting conditions arefunctional for said probe to hybridize specifically to nucleic acid insaid sample.

[0062] The phrase “hybridize specifically”indicates that thehybridization between single-stranded polynucleotides is based onnucleotide sequence complementarity. The effective conditions areselected such that the probe hybridizes to a preselected and/or definitetarget nucleic acid in the sample. For instance, if detection of apolynucleotide set forth in SEQ ID NO 1, 3, 5, 7, 9, and others isdesired, a probe can be selected which can hybridize to such target geneunder high stringent conditions, without significant hybridization toother genes in the sample. To detect homologs of a polynucleotide setforth in SEQ ID NO 1, 3, 5, 7, 9, and others, the effectivehybridization conditions can be less stringent, and/or the probe cancomprise codon degeneracy, such that a homolog is detected in thesample.

[0063] As already mentioned, the methods can be carried out by anyeffective process, e.g., by Northern blot analysis, polymerase chainreaction (PCR), reverse transcriptase PCR, RACE PCR, in situhybridization, etc., as indicated above. When PCR based techniques areused, two or more probes are generally used. One probe can be specificfor a defined sequence which is characteristic of a selectivepolynucleotide, but the other probe can be specific for the selectivepolynucleotide, or specific for a more general sequence, e.g., asequence such as polyA which is characteristic of mRNA, a sequence whichis specific for a promoter, ribosome binding site, or othertranscriptional features, a consensus sequence (e.g., representing afunctional domain). For the former aspects, 5′ and 3′ probes (e.g.,polyA, Kozak, etc.) are preferred which are capable of specificallyhybridizing to the ends of transcripts. When PCR is utilized, the probescan also be referred to as “primers” in that they can prime a DNApolymerase reaction.

[0064] In addition to testing for the presence or absence ofpolynucleotides, the present invention also relates to determining theamounts at which polynucleotides of the present invention are expressedin sample and determining the differential expression of suchpolynucleotides in samples.. Such methods can involve substantially thesame steps as described above for presence/absence detection, e.g.,contacting with probe, hybridizing, and detecting hybridized probe, butusing more quantitative methods and/or comparisons to standards.

[0065] The amount of hybridization between the probe and target can bedetermined by any suitable methods, e.g., PCR, RT-PCR, RACE PCR,Northern blot, polynucleotide microarrays, Rapid-Scan, etc., andincludes both quantitative and qualitative measurements. For furtherdetails, see the hybridization methods described above and below.Determining by such hybridization whether the target is differentiallyexpressed (e.g., up-regulated or down-regulated) in the sample can alsobe accomplished by any effective means. For instance, the target'sexpression pattern in the sample can be compared to its pattern in aknown standard, such as in a normal tissue, or it can be compared toanother gene in the same sample. When a second sample is utilized forthe comparison, it can be a sample of normal tissue that is known not tocontain diseased cells. The comparison can be performed on samples whichcontain the same amount of RNA (such as polyadenylated RNA or totalRNA), or, on RNA extracted from the same amounts of starting tissue.Such a second sample can also be referred to as a control or standard.Hybridization can also be compared to a second target in the same tissuesample. Experiments can be performed that determine a ratio between thetarget nucleic acid and a second nucleic acid (a standard or control) ,e.g., in a normal tissue. When the ratio between the target and controlare substantially the same in a normal and sample, the sample isdetermined or diagnosed not to contain cells. However, if the ratio isdifferent between the normal and sample tissues, the sample isdetermined to contain cancer cells. The approaches can be combined, andone or more second samples, or second targets can be used. Any secondtarget nucleic acid can be used as a comparison, including“housekeeping” genes, such as beta-actin, alcohol dehydrogenase, or anyother gene whose expression does not vary depending upon the diseasestatus of the cell.

[0066] Methods of Identifying Polymorphisms, Mutations, etc., of HumanTARPP

[0067] Polynucleotides of the present invention can also be utilized toidentify mutant alleles, SNPs, gene rearrangements and modifications,and other polymorphisms of the wild-type gene. Mutant alleles,polymorphisms, SNPs, etc., can be identified and isolated from cancersthat are known, or suspected to have, a genetic component.Identification of such genes can be carried out routinely (see, abovefor more guidance), e.g., using PCR, hybridization techniques, directsequencing, mismatch reactions (see, e.g., above), RFLP analysis, SSCP(e.g., Orita et al., Proc. Natl. Acad. Sci., 86:2766, 1992), etc., wherea polynucleotide having a sequence selected from SEQ ID NO 1, 3, 5, 7,9, and others is used as a probe. The selected mutant alleles, SNPs,polymorphisms, etc., can be used diagnostically to determine whether asubject has, or is susceptible to a disorder associated with humanTARPP, as well as to design therapies and predict the outcome of thedisorder. Methods involve, e.g., diagnosing a disorder associated withhuman TARPP or determining susceptibility to a disorder, comprising,detecting the presence of a mutation in a gene represented by apolynucleotide selected from SEQ ID NO 1, 3, 5, 7, 9, and others. Thedetecting can be carried out by any effective method, e.g., obtainingcells from a subject, determining the gene sequence or structure of atarget gene (using, e.g., mRNA, cDNA, genomic DNA, etc), comparing thesequence or structure of the target gene to the structure of the normalgene, whereby a difference in sequence or structure indicates a mutationin the gene in the subject. Polynucleotides can also be used to test formutations, SNPs, polymorphisms, etc., e.g., using mismatch DNA repairtechnology as described in U.S. Pat. Nos. 5,683,877; 5,656,430; Wu etal., Proc. Natl. Acad. Sci., 89:8779-8783, 1992.

[0068] The present invention also relates to methods of detectingpolymorphisms in human TARPP, comprising, e.g., comparing the structureof: genomic DNA comprising all or part of human TARPP, mRNA comprisingall or part of human TARPP, cDNA comprising all or part of human TARPP,or a polypeptide comprising all or part of human TARPP, with thestructure of human TARPP set forth in SEQ ID NOS. 1-8. The methods canbe carried out on a sample from any source, e.g., cells, tissues, bodyfluids, blood, urine, stool, hair, egg, sperm, cerebral spinal fluid,etc.

[0069] These methods can be implemented in many different ways. Forexample, “comparing the structure” steps include, but are not limitedto, comparing restriction maps, nucleotide sequences, amino acidsequences, RFLPs, Dnase sites, DNA methylation fingerprints (e.g., U.S.Pat. No. 6,214,556), protein cleavage sites, molecular weights,electrophoretic mobilities, charges, ion mobility, etc., between astandard human TARPP and a test human TARPP. The term “structure” canrefer to any physical characteristics or configurations which can beused to distinguish between nucleic acids and polypeptides. The methodsand instruments used to accomplish the comparing step depends upon thephysical characteristics which are to be compared. Thus, varioustechniques are contemplated, including, e.g., sequencing machines (bothamino acid and polynucleotide), electrophoresis, mass spectrometer (U.S.Pat. Nos. 6,093,541, 6,002,127), liquid chromatography, HPLC, etc.

[0070] To carry out such methods, “all or part” of the gene orpolypeptide can be compared. For example, if nucleotide sequencing isutilized, the entire gene can be sequenced, including promoter, introns,and exons, or only parts of it can be sequenced and compared, e.g., exon1, exon 2, etc.

[0071] Mutagenesis

[0072] Mutated polynucleotide sequences of the present invention areuseful for various purposes, e.g., to create mutations of thepolypeptides they encode, to identify functional regions of genomic DNA,to produce probes for screening libraries, etc. Mutagenesis can becarried out routinely according to any effective method, e.g.,oligonucleotide-directed (Smith, M., Ann. Rev. Genet. 19:423-463, 1985),degenerate oligonucleotide-directed (Hill et al., Method Enzymology,155:558-568, 1987), region-specific (Myers et al., Science, 229:242-246,1985; Derbyshire et al., Gene, 46:145, 1986; Ner et al., DNA, 7:127,1988), linker-scanning (McKnight and Kingsbury, Science, 217:316-324,1982), directed using PCR, recursive ensemble mutagenesis (Arkin andYourvan, Proc. Natl. Acad. Sci., 89:7811-7815, 1992), random mutagenesis(e.g., U.S. Pat. Nos. 5,096,815; 5,198,346; and 5,223,409),site-directed mutagenesis (e.g., Walder et al., Gene, 42:133, 1986;Bauer et al., Gene, 37:73, 1985; Craik, Bio Techniques, Jan. 12-19,1985; Smith et al., Genetic Engineering: Principles and Methods, PlenumPress, 1981), phage display (e.g., Lowman et al., Biochem.30:10832-10837, 1991; Ladner et al., U.S. Pat. No. 5,223,409; Huse, WIPOPublication WO 92/06204), etc. Desired sequences can also be produced bythe assembly of target sequences using mutually priming oligonucleotides(Uhlmann, Gene, 71:29-40, 1988). For directed mutagenesis methods,analysis of the three-dimensional structure of the human TARPPpolypeptide can be used to guide and facilitate making mutants whicheffect polypeptide activity. Sites of substrate-enzyme interaction orother biological activities can also be determined by analysis ofcrystal structure as determined by such techniques as nuclear magneticresonance, crystallography or photoaffinity labeling. See, for example,de Vos et al., Science 255:306-312, 1992; Smith et al., J. Mol. Biol.224:899-904, 1992; Wlodaver et al., FEBS Lett. 309:59-64, 1992.

[0073] In addition, libraries of human TARPP and fragments thereof canbe used for screening and selection of human TARPP variants. Forinstance, a library of coding sequences can be generated by treating adouble-stranded DNA with a nuclease under conditions where the nickingoccurs, e.g., only once per molecule, denaturing the double-strandedDNA, renaturing it to for double-stranded DNA that can includesense/antisense pairs from different nicked products, removingsingle-stranded portions from reformed duplexes by treatment with S1nuclease, and ligating the resulting DNAs into an expression vector. Bythis method, expression libraries can be made comprising “mutagenized”human TARPP. The entire coding sequence or parts thereof can be used.

[0074] Polynucleotide Expression, Polypeptides Produced Thereby, andSpecific-binding Partners thereto.

[0075] A polynucleotide according to the present invention can beexpressed in a variety of different systems, in vitro and in vivo,according to the desired purpose. For example, a polynucleotide can beinserted into an expression vector, introduced into a desired host, andcultured under conditions effective to achieve expression of apolypeptide coded for by the polynucleotide, to search for specificbinding partners. Effective conditions include any culture conditionswhich are suitable for achieving production of the polypeptide by thehost cell, including effective temperatures, pH, medium, additives tothe media in which the host cell is cultured (e.g., additives whichamplify or induce expression such as butyrate, or methotrexate if thecoding polynucleotide is adjacent to a dhfr gene), cycloheximide, celldensities, culture dishes, etc. A polynucleotide can be introduced intothe cell by any effective method including, e.g., naked DNA, calciumphosphate precipitation, electroporation, injection, DEAE-Dextranmediated transfection, fusion with liposomes, association with agentswhich enhance its uptake into cells, viral transfection. A cell intowhich a polynucleotide of the present invention has been introduced is atransformed host cell. The polynucleotide can be extrachromosomal orintegrated into a chromosome(s) of the host cell. It can be stable ortransient. An expression vector is selected for its compatibility withthe host cell. Host cells include, mammalian cells, e.g., COS, CV1, BHK,CHO, HeLa, LTK, NIH 3T3, CNS neural stem cells (e.g., U.S. Pat. No.6,103,530), IMR-32, A172 (ATCC CRL-1620), T98G (ATCC CRL-1690),CCF-STTG1 (ATCC CRL-1718), DBTRG-05MG (ATCC CRL-2020), PFSK-1 (ATCCCRL-2060), SK-N-AS and other SK cell lines (ATCC CRL-2137), CHP-212(ATCC CRL-2273), RG2 (ATCC CRL-2433), HCN-2 (ATCC CRL-10742), U-87 MGand other U MG cell lines (ATCC HTB-14), D283 Med (ATCC HTB-185), PC 12,Neuro-2a (ATCC CCL-131), HH (ATCC CRL 2105), MOLT-4 (ATCC CRL 1582), MJ(ATCC CRL-8294), SK7 (ATCC HB-8584), SK8 (ATCC HB-8585), HM1 (HB-8586),H9 (ATCC HTB-176), HuT 78 (ATCC TIB-161), HuT 102 (ATCC TIB-162),Jurkat, insect cells, such as Sf9 (S. frugipeda) and Drosophila,bacteria, such as E. coli, Streptococcus, bacillus, yeast, such asSacharomyces, S. cerevisiae, fungal cells, plant cells, embryonic oradult stem cells (e.g., mammalian, such as mouse or human).

[0076] Expression control sequences are similarly selected for hostcompatibility and a desired purpose, e.g., high copy number, highamounts, induction, amplification, controlled expression. Othersequences which can be employed include enhancers such as from SV40,CMV, RSV, inducible promoters, cell-type specific elements, or sequenceswhich allow selective or specific cell expression. Promoters that can beused to drive its expression, include, e.g., the endogenous promoter,MMTV, SV40, trp, lac, tac, or T7 promoters for bacterial hosts; or alphafactor, alcohol oxidase, or PGH promoters for yeast. RNA promoters canbe used to produced RNA transcripts, such as T7 or SP6. See, e.g.,Melton et al., Polynucleotide Res., 12(18):7035-7056, 1984; Dunn andStudier. J. Mol. Bio., 166:477-435, 1984; U.S. Pat. No. 5,891,636;Studier et al., Gene Expression Technology, Methods in Enzymology,85:60-89, 1987. In addition, as discussed above, translational signals(including in-frame insertions) can be included.

[0077] When a polynucleotide is expressed as a heterologous gene in atransfected cell line, the gene is introduced into a cell as describedabove, under effective conditions in which the gene is expressed. Theterm “heterologous” means that the gene has been introduced into thecell line by the “hand-of-man.” Introduction of a gene into a cell lineis discussed above. The transfected (or transformed) cell expressing thegene can be lysed or the cell line can be used intact.

[0078] For expression and other purposes, a polynucleotide can containcodons found in a naturally-occurring gene, transcript, or cDNA, forexample, e.g., as set forth in SEQ ID NO 1, 3, 5, 7, 9, and others, orit can contain degenerate codons coding for the same amino acidsequences. For instance, it may be desirable to change the codons in thesequence to optimize the sequence for expression in a desired host. See,e.g., U.S. Pat. Nos. 5,567,600 and 5,567,862.

[0079] A polypeptide according to the present invention can be recoveredfrom natural sources, transformed host cells (culture medium or cells)according to the usual methods, including, detergent extraction (e.g.,non-ionic detergent, Triton X-100, CHAPS, octylglucoside, IgepalCA-630), ammonium sulfate or ethanol precipitation, acid extraction,anion or cation exchange chromatography, phosphocellulosechromatography, hydrophobic interaction chromatography, hydroxyapatitechromatography, lectin chromatography, gel electrophoresis. Proteinrefolding steps can be used, as necessary, in completing theconfiguration of the mature protein. Finally, high performance liquidchromatography (HPLC) can be employed for purification steps. Anotherapproach is express the polypeptide recombinantly with an affinity tag(Flag epitope, HA epitope, myc epitope, 6×His, maltose binding protein,chitinase, etc) and then purify by anti-tag antibody-conjugated affinitychromatography.

[0080] The present invention also relates to antibodies, and otherspecific-binding partners, which are specific for polypeptides encodedby polynucleotides of the present invention, e.g., human TARPP.Antibodies, e.g., polyclonal, monoclonal, recombinant, chimeric,humanized, single-chain, Fab, and fragments thereof, can be preparedaccording to any desired method. See, also, screening recombinantimmunoglobulin libraries (e.g., Orlandi et al., Proc. Natl. Acad. Sci.,86:3833-3837, 1989; Huse et al., Science, 256:1275-1281, 1989); in vitrostimulation of lymphocyte populations; Winter and Milstein, Nature, 349:293-299, 1991. The antibodies can be IgM, IgG, subtypes, IgG2a, IgG1,etc. Antibodies, and immune responses, can also be generated byadministering naked DNA See, e.g., U.S. Pat. Nos. 5,703,055; 5,589,466;5,580,859. Antibodies can be used from any source, including, goat,rabbit, mouse, chicken (e.g., IgY; see, Duan, W0/029444 for methods ofmaking antibodies in avian hosts, and harvesting the antibodies from theeggs). An antibody specific for a polypeptide means that the antibodyrecognizes a defined sequence of amino acids within or including thepolypeptide. Other specific binding partners include, e.g., aptamers andPNA. antibodies can be prepared against specific epitopes or domains ofhuman TARPP, e.g., 1-161, 88-161, 267-300, 312-331, comprising aminoacid 312, and comprising any of the amino acid differences between mouseand human as shown in FIG. 3.

[0081] The preparation of polyclonal antibodies is well-known to thoseskilled in the art. See, for example, Green et al., Production ofPolyclonal Antisera, in IMMUNOCHEMICAL PROTOCOLS (Manson, ed.), pages1-5 (Humana Press 1992); Coligan et al., Production of PolyclonalAntisera in Rabbits, Rats, Mice and Hamsters, in CURRENT PROTOCOLS INIMMUNOLOGY, section 2.4.1 (1992). The preparation of monoclonalantibodies likewise is conventional. See, for example, Kohler &Milstein, Nature 256:495 (1975); Coligan et al., sections 2.5.1-2.6.7;and Harlow et al., ANTIBODIES: A LABORATORY MANUAL, page 726 (ColdSpring Harbor Pub. 1988).

[0082] Antibodies can also be humanized, e.g., where they are to be usedtherapeutically. Humanized monoclonal antibodies are produced bytransferring mouse complementarity determining regions from heavy andlight variable chains of the mouse immunoglobulin into a human variabledomain, and then substituting human residues in the framework regions ofthe murine counterparts. The use of antibody components derived fromhumanized monoclonal antibodies obviates potential problems associatedwith the immunogenicity of murine constant regions. General techniquesfor cloning murine immunoglobulin variable domains are described, forexample, by Orlandi et al., Proc. Nat'l Acad. Sci. USA 86:3833 (1989),which is hereby incorporated in its entirety by reference. Techniquesfor producing humanized monoclonal antibodies are described, forexample, in U.S. Pat. No. 6,054,297, Jones et al., Nature 321: 522(1986); Riechmann et al., Nature 332: 323 (1988); Verhoeyen et al.,Science 239: 1534 (1988); Carter et al., Proc. Nat'l Acad. Sci. USA 89:4285 (1992); Sandhu, Crit. Rev. Biotech. 12: 437 (1992); and Singer etal., J. Immunol. 150: 2844 (1993).

[0083] Antibodies of the invention also may be derived from humanantibody fragments isolated from a combinatorial immunoglobulin library.See, for example, Barbas et al., METHODS: A COMPANION TO METHODS INENZYMOLOGY, VOL. 2, page 119 (1991); Winter et al., Ann. Rev. Immunol.12: 433 (1994). Cloning and expression vectors that are useful forproducing a human immunoglobulin phage library can be obtainedcommercially, for example, from STRATAGENE Cloning Systems (La Jolla,Calif.).

[0084] In addition, antibodies of the present invention may be derivedfrom a human monoclonal antibody. Such antibodies are obtained fromtransgenic mice that have been “engineered” to produce specific humanantibodies in response to antigenic challenge. In this technique,elements of the human heavy and light chain loci are introduced intostrains of mice derived from embryonic stem cell lines that containtargeted disruptions of the endogenous heavy and light chain loci. Thetransgenic mice can synthesize human antibodies specific for humanantigens and can be used to produce human antibody-secreting hybridomas.Methods for obtaining human antibodies from transgenic mice aredescribed, e.g., in Green et al., Nature Genet. 7:13 (1994); Lonberg etal., Nature 368:856 (1994); and Taylor et al., Int. Immunol. 6:579(1994).

[0085] Antibody fragments of the present invention can be prepared byproteolytic hydrolysis of the antibody or by expression in E. coli ofnucleic acid encoding the fragment. Antibody fragments can be obtainedby pepsin or papain digestion of whole antibodies by conventionalmethods. For example, antibody fragments can be produced by enzymaticcleavage of antibodies with pepsin to provide a 5S fragment denotedF(ab′).sub.2. This fragment can be further cleaved using a thiolreducing agent, and optionally a blocking group for the sulfhydrylgroups resulting from cleavage of disulfide linkages, to produce 3.5SFab′ monovalent fragments. Alternatively, an enzymatic cleavage usingpepsin produces two monovalent Fab′ fragments and an Fc fragmentdirectly. These methods are described, for example, by Goldenberg, U.S.Pat. Nos. 4,036,945 and 4,331,647, and references contained therein.These patents are hereby incorporated in their entireties by reference.See also Nisoiihoff et al., Arch. Biochem. Biophys. 89:230 (1960);Porter, Biochem. J. 73:119 (1959); Edelman etal, METHODS IN ENZYMOLOGY,VOL. 1, page 422 (Academic Press 1967); and Coligan et al. at sections2.8.1-2.8.10 and 2.10.1-2.10.4.

[0086] Other methods of cleaving antibodies, such as separation of heavychains to form monovalent light-heavy chain fragments, further cleavageof fragments, or other enzymatic, chemical, or genetic techniques canalso be used. For example, Fv fragments comprise an association ofV.sub.H and V.sub.L chains. This association may be noncovalent, asdescribed in Inbar et al., Proc. Nat'l Acad. Sci. USA 69:2659 (1972).Alternatively, the variable chains can be linked by an intermoleculardisulfide bond or cross-linked by chemicals such as glutaraldehyde. See,e.g., Sandhu, supra. Preferably, the Fv fragments comprise V.sub.H andV.sub.L chains connected by a peptide linker. These single-chain antigenbinding proteins (sFv) are prepared by constructing a structural genecomprising nucleic acid sequences encoding the V.sub.H and V.sub.Ldomains connected by an oligonucleotide. The structural gene is insertedinto an expression vector, which is subsequently introduced into a hostcell such as E. coli. The recombinant host cells synthesize a singlepolypeptide chain with a linker peptide bridging the two V domains.Methods for producing sFvs are described, for example, by Whitlow etal., METHODS: A COMPANION TO METHODS IN ENZYMOLOGY, VOL. 2, page 97(1991); Bird etal.,Science 242:423-426 (1988); Ladneret al., U.S. Pat.No. 4,946,778; Pack et al., Bio/Technology 11: 1271-77 (1993); andSandhu, supra.

[0087] Another form of an antibody fragment is a peptide coding for asingle complementarity-determining region (CDR). CDR peptides (“minimalrecognition units”) can be obtained by constructing genes encoding theCDR of an antibody of interest. Such genes are prepared, for example, byusing the polymerase chain reaction to synthesize the variable regionfrom RNA of antibody-producing cells. See, for example, Lariick et al.,METHODS: A COMPANION TO METHODS IN ENZYMOLOGY, VOL. 2, page 106 (1991).

[0088] The term “antibody” as used herein includes intact molecules aswell as fragments thereof, such as Fab, F(ab′)2, and Fv which arecapable of binding to an epitopic determinant present in BinIpolypeptide. Such antibody fragments retain some ability to selectivelybind with its antigen or receptor. The term “epitope” refers to anantigenic determinant on an antigen to which the paratope of an antibodybinds. Epitopic determinants usually consist of chemically activesurface groupings of molecules such as amino acids or sugar side chainsand usually have specific three dimensional structural characteristics,as well as specific charge characteristics. Antibodies can be preparedagainst specific epitopes or polypeptide domains.

[0089] Antibodies which bind to human TARPP polypeptides of the presentinvention can be prepared using an intact polypeptide or fragmentscontaining small peptides of interest as the immunizing antigen. Forexample, it may be desirable to produce antibodies that specificallybind to the N- or C-terminal domains of human TARPP. The polypeptide orpeptide used to immunize an animal which is derived from translated cDNAor chemically synthesized which can be conjugated to a carrier protein,if desired. Such commonly used carriers which are chemically coupled tothe immunizing peptide include keyhole limpet hemocyanin (KLH),thyroglobulin, bovine serum albumin (BSA), and tetanus toxoid.

[0090] Polyclonal or monoclonal antibodies can be further purified, forexample, by binding to and elution from a matrix to which thepolypeptide or a peptide to which the antibodies were raised is bound.Those of skill in the art will know of various techniques common in theimmunology arts for purification and/or concentration of polyclonalantibodies, as well as monoclonal antibodies (See for example, Coligan,et al., Unit 9, Current Protocols in Immunology, Wiley Interscience,1994, incorporated by reference).

[0091] Anti-idiotype technology can also be used to produce inventionmonoclonal antibodies which mimic an epitope. For example, ananti-idiotypic monoclonal antibody made to a first monoclonal antibodywill have a binding domain in the hypervariable region which is the“image” of the epitope bound by the first monoclonal antibody.

[0092] Methods of Detecting Polypeptides

[0093] Polypeptides coded for by human TARPP of the present inventioncan be detected, visualized, determined, quantitated, etc. according toany effective method. useful methods include, e.g., but are not limitedto, immunoassays, RIA (radioimmunassay), ELISA,(enzyme-linked-immunosorbent assay), immunoflourescence, flow cytometry,histology, electron microscopy, light microscopy, in situ assays,immunoprecipitation, Western blot.

[0094] Immunoassays may be carried in liquid or on biological support.For instance, a sample (e.g., blood, stool, urine, cells, tissue,cerebral spinal fluid, body fluids, etc.) can be brought in contact withand immobilized onto a solid phase support or carrier such asnitrocellulose, or other solid support that is capable of immobilizingcells, cell particles or soluble proteins. The support may then bewashed with suitable buffers followed by treatment with the detectablylabeled human TARPP specific antibody. The solid phase support can thenbe washed with a buffer a second time to remove unbound antibody. Theamount of bound label on solid support may then be detected byconventional means.

[0095] A “solid phase support or carrier” includes any support capableof binding an antigen, antibody, or other specific binding partner.Supports or carriers include glass, polystyrene, polypropylene,polyethylene, dextran, nylon, amylases, natural and modified celluloses,polyacrylamides, and magnetite. A support material can have anystructural or physical configuration. Thus, the support configurationmay be spherical, as in a bead, or cylindrical, as in the inside surfaceof a test tube, or the external surface of a rod. Alternatively, thesurface may be flat such as a sheet, test strip, etc. Preferred supportsinclude polystyrene beads

[0096] One of the many ways in which gene peptide-specific antibody canbe detectably labeled is by linking it to an enzyme and using it in anenzyme immunoassay (EIA). See, e.g., Voller, A., “The Enzyme LinkedImmunosorbent Assay (ELISA),” 1978, Diagnostic Horizons 2, 1-7,Microbiological Associates Quarterly Publication, Walkersville, Md.);Voller, A. et al., 1978, J. Clin. Pathol. 31, 507-520; Butler, J. E.,1981, Meth. Enzymol. 73, 482-523; Maggio, E. (ed.), 1980, EnzymeImmunoassay, CRC Press, Boca Raton, Fla. The enzyme which is bound tothe antibody will react with an appropriate substrate, preferably achromogenic substrate, in such a manner as to produce a chemical moietythat can be detected, for example, by spectrophotometric, fluorimetricor by visual means. Enzymes that can be used to detectably label theantibody include, but are not limited to, malate dehydrogenase,staphylococcal nuclease, delta-5-steroid isomerase, yeast alcoholdehydrogenase, .alpha.-glycerophosphate, dehydrogenase, triose phosphateisomerase, horseradish peroxidase, alkaline phosphatase, asparaginase,glucose oxidase, beta.-galactosidase, ribonuclease, urease, catalase,glucose-6-phosphate dehydrogenase, glucoamylase andacetylcholinesterase. The detection can be accomplished by calorimetricmethods that employ a chromogenic substrate for the enzyme. Detectionmay also be accomplished by visual comparison of the extent of enzymaticreaction of a substrate in comparison with similarly prepared standards.

[0097] Detection may also be accomplished using any of a variety ofother immunoassays. For example, by radioactively labeling theantibodies or antibody fragments, it is possible to detect human TARPPpeptides through the use of a radioimmunoassay (RIA). See, e.g.,Weintraub, B., Principles of Radioimmunoassays, Seventh Training Courseon Radioligand Assay Techniques, The Endocrine Society, March, 1986. Theradioactive isotope can be detected by such means as the use of a gammacounter or a scintillation counter or by autoradiography.

[0098] It is also possible to label the antibody with a fluorescentcompound. When the fluorescently labeled antibody is exposed to light ofthe proper wave length, its presence can then be detected due tofluorescence. Among the most commonly used fluorescent labelingcompounds are fluorescein isothiocyanate, rhodamine, phycoerythrin,phycocyanin, allophycocyanin, o-phthaldehyde and fluorescamine. Theantibody can also be detectably labeled using fluorescence emittingmetals such as those in the lanthanide series. These metals can beattached to the antibody using such metal chelating groups asdiethylenetriaminepentacetic acid (DTPA) or ethylenediaminetetraaceticacid (EDTA).

[0099] The antibody also can be detectably labeled by coupling it to achemiluminescent compound. The presence of the chemiluminescent-taggedantibody is then determined by detecting the presence of luminescencethat arises during the course of a chemical reaction. Examples of usefulchemiluminescent labeling compounds are luminol, isoluminol, theromaticacridinium ester, imidazole, acridinium salt and oxalate ester.

[0100] Likewise, a bioluminescent compound may be used to label theantibody of the present invention. Bioluminescence is a type ofchemiluminescence found in biological systems in which a catalyticprotein increases the efficiency of the chemiluminescent reaction. Thepresence of a bioluminescent protein is determined by detecting thepresence of luminescence. Important bioluminescent compounds forpurposes of labeling are luciferin, luciferase and aequorin.

[0101] Diagnostic

[0102] The present invention also relates to methods and compositionsfor diagnosing a disorder of nervous or immune (e.g., lymphocyte)tissues, or determining susceptibility to a disorder, usingpolynucleotides, polypeptides, and specific-binding partners of thepresent invention to detect, assess, determine, etc., human TARPP. Insuch methods, the gene can serve as a marker for the disorder, e.g.,where the gene, when mutant, is a direct cause of the disorder; wherethe gene is affected by another gene(s) which is directly responsiblefor the disorder, e.g., when the gene is part of the same signalingpathway as the directly responsible gene; and, where the gene ischromosomally linked to the gene(s) directly responsible for thedisorder, and segregates with it. Many other situations are possible. Todetect, assess, determine, etc., a probe specific for the gene can beemployed as described above and below. Any method of detecting and/orassessing the gene can be used, including detecting expression of thegene using polynucleotides, antibodies, or other specific-bindingpartners.

[0103] The present invention relates to methods of diagnosing a disorderassociated with human TARPP, or determining a subject's susceptibilityto such disorder, comprising, e.g., assessing the expression of saidgene(s) in a tissue sample comprising tissue or cells suspected ofhaving the disorder. The phrase “diagnosing” indicates that it isdetermined whether the sample has the disorder. A “disorder” means,e.g., any abnormal condition as in a disease or malady. “Determining asubject's susceptibility to a disease or disorder” indicates that thesubject is assessed for whether she is predisposed to get such a diseaseor disorder, where the predisposition is indicated by abnormalexpression of the gene (e.g., gene mutation, gene expression pattern isnot normal, etc.). Predisposition or susceptibility to a disease mayresult when a such disease is influenced by epigenetic, environmental,etc., factors. This includes prenatal screening where samples from thefetus or embryo (e.g., via amniocentesis or CV sampling) are analyzedfor the expression of the gene.

[0104] By the phrase “assessing expression of human TARPP,” it is meantthat the functional status of the gene is evaluated. This includes, butis not limited to, measuring expression levels of said gene, determiningthe genomic structure of said gene, determining the mRNA structure oftranscripts from said gene, or measuring the expression levels ofpolypeptide coded for by said gene. Thus, the term “assessingexpression” includes evaluating the all aspects of the transcriptionaland translational machinery of the gene. For instance, if a promoterdefect causes, or is suspected of causing, the disorder, then a samplecan be evaluated (i.e., “assessed”) by looking (e.g., sequencing orrestriction mapping) at the promoter sequence in the gene, by detectingtranscription products (e.g., RNA), by detecting translation product(e.g., polypeptide). Any measure of whether the gene is functional canbe used, including, polypeptide, polynucleotide, and functional assaysfor the gene's biological activity.

[0105] In making the assessment, it can be useful to compare the resultsto a normal gene, e.g., a gene which is not associated with thedisorder. The nature of the comparison can be determined routinely,depending upon how the assessing is accomplished. If, for example, themRNA levels of a sample is detected, then the mRNA levels of a normalcan serve as a comparison, or a gene which is known not to be affectedby the disorder. Methods of detecting mRNA are well known, and discussedabove, e.g., but not limited to, Northern blot analysis, polymerasechain reaction (PCR), reverse transcriptase PCR, RACE PCR, etc.Similarly, if polypeptide production is used to evaluate the gene, thenthe polypeptide in a normal tissue sample can be used as a comparison,or, polypeptide from a different gene whose expression is known not tobe affected by the disorder. These are only examples of how such amethod could be carried out.

[0106] Assessing the effects of therapeutic and preventativeinterventions (e.g., administration of a drug, chemotherapy, radiation,etc.) on nervous and immune disorders is a major effort in drugdiscovery, clinical medicine, and pharmacogenomics. The evaluation oftherapeutic and preventative measures, whether experimental or alreadyin clinical use, has broad applicability, e.g., in clinical trials, formonitoring the status of a patient, for analyzing and assessing animalmodels, and in any scenario involving cancer treatment and prevention.Analyzing the expression profiles of polynucleotides of the presentinvention can be utilized as a parameter by which interventions arejudged and measured. Treatment of a disorder can change the expressionprofile in some manner which is prognostic or indicative of the drug'seffect on it. Changes in the profile can indicate, e.g., drug toxicity,return to a normal level, etc. Accordingly, the present invention alsorelates to methods of monitoring or assessing a therapeutic orpreventative measure (e.g., chemotherapy, radiation, anti-neoplasticdrugs, antibodies, etc.) in a subject, comprising, e.g., detecting theexpression levels of human TARPP. A subject can be a cell-based assaysystem, non-human animal model, human patient, etc. Detecting can beaccomplished as described for the methods above and below. By“therapeutic or preventative intervention,” it is meant, e.g., a drugadministered to a patient, surgery, radiation, chemotherapy, and othermeasures taken to prevent, treat, or diagnose a disorder.

[0107] Expression can be assessed in any sample comprising any tissue orcell type, body fluid, etc., as discussed for other methods of thepresent invention, including cells from the immune or nervous system,such as lymphocytes, neurons, or glia

[0108] Identifying Agent Methods

[0109] The present invention also relates to methods of identifyingagents, and the agents themselves, which modulate human TARPP. Theseagents can be used to modulate the biological activity of thepolypeptide encoded for the gene, or the gene, itself. Agents whichregulate the gene or its product are useful in variety of differentenvironments, including as medicinal agents to treat or preventdisorders associated with human TARPP and as research reagents to modifythe function of tissues and cell.

[0110] Methods of identifying agents generally comprise steps in whichan agent is placed in contact with the gene, transcription product,translation product, or other target, and then a determination isperformed to assess whether the agent “modulates” the target. Thespecific method utilized will depend upon a number of factors,including, e.g., the target (i.e., is it the gene or polypeptide encodedby it), the environment (e.g., in vitro or in vivo), the composition ofthe agent, etc.

[0111] For modulating the expression of human TARPP gene, a method cancomprise, in any effective order, one or more of the following steps,e.g., contacting a human TARPP gene (e.g., in a cell population) with atest agent under conditions effective for said test agent to modulatethe expression of human TARPP, and determining whether said test agentmodulates said human TARPP. An agent can modulate expression of humanTARPP at any level, including transcription, translation, and/orperdurance of the nucleic acid (e.g., degradation, stability, etc.) inthe cell.

[0112] For modulating the biological activity of human TARPPpolypeptides, a method can comprise, in any effective order, one or moreof the following steps, e.g., contacting a human TARPP polypeptide(e.g., in a cell, lysate, or isolated) with a test agent underconditions effective for said test agent to modulate the biologicalactivity of said polypeptide, and determining whether said test agentmodulates said biological activity.

[0113] Contacting human TARPP with the test agent can be accomplished byany suitable method and/or means that places the agent in a position tofunctionally control expression or biological activity of human TARPPpresent in the sample. Functional control indicates that the agent canexert its physiological effect on human TARPP through whatever mechanismit works. The choice of the method and/or means can depend upon thenature of the agent and the condition and type of environment in whichthe human TARPP is presented, e.g., lysate, isolated, or in a cellpopulation (such as, in vivo, in vitro, organ explants, etc.). Forinstance, if the cell population is an in vitro cell culture, the agentcan be contacted with the cells by adding it directly into the culturemedium. If the agent cannot dissolve readily in an aqueous medium, itcan be incorporated into liposomes, or another lipophilic carrier, andthen administered to the cell culture. Contact can also be facilitatedby incorporation of agent with carriers and delivery molecules andcomplexes, by injection, by infusion, etc.

[0114] After the agent has been administered in such a way that it cangain access to human TARPP, it can be determined whether the test agentmodulates human TARPP expression or biological activity. Modulation canbe of any type, quality, or quantity, e.g., increase, facilitate,enhance, up-regulate, stimulate, activate, amplify, augment, induce,decrease, down-regulate, diminish, lessen, reduce, etc. The modulatoryquantity can also encompass any value, e.g., 1%, 5%, 10%, 50%, 75%,1-fold, 2-fold, 5-fold, 10-fold, 100-fold, modulate human TARPPexpression means, e.g., that the test agent has an effect on itsexpression, e.g., to effect the amount of transcription, to effect RNAsplicing, to effect translation of the RNA into polypeptide, to effectRNA or polypeptide stability, to effect polyadenylation or otherprocessing of the RNA, to effect post-transcriptional orpost-translational processing, etc. To modulate biological activitymeans, e.g., that a functional activity of the polypeptide is changed incomparison to its normal activity in the absence of the agent. Thiseffect includes, increase, decrease, block, inhibit, enhance, etc.Biological activities of human TARPP included, e.g., nucleic acidbinding activity.

[0115] A test agent can be of any molecular composition, e.g., chemicalcompounds, biomolecules, such as polypeptides, lipids, nucleic acids(e.g., antisense to a polynucleotide sequence selected from SEQ ID NO 1,3, 5, 7, 9, and others), carbohydrates, antibodies, ribozymes,double-stranded RNA, aptamers, etc. For example, if a polypeptide to bemodulated is a cell-surface molecule, a test agent can be an antibodythat specifically recognizes it and, e.g., causes the polypeptide to beinternalized, leading to its down regulation on the surface of the cell.Such an effect does not have to be permanent, but can require thepresence of the antibody to continue the down-regulatory effect.Antibodies can also be used to modulate the biological activity apolypeptide in a lysate or other cell-free form. Antisense human TARPPcan also be used as test agents to modulate gene expression.

[0116] Therapeutics

[0117] Selective polynucleotides, polypeptides, and specific-bindingpartners thereto, can be utilized in therapeutic applications,especially to treat diseases and conditions of the immune and nervoussystem. Useful methods include, but are not limited to, immunotherapy(e.g., using specific-binding partners to polypeptides), vaccination(e.g., using a selective polypeptide or a naked DNA encoding suchpolypeptide), protein or polypeptide replacement therapy, gene therapy(e.g., germ-line correction, antisense), etc.

[0118] Various immunotherapeutic approaches can be used. For instance,unlabeled antibody that specifically recognizes a tissue-specificantigen can be used to stimulate the body to destroy or attack thecancer, to cause down-regulation, to produce complement-mediated lysis,to inhibit cell growth, etc., of target cells which display the antigen,e.g., analogously to how c-erbB-2 antibodies are used to treat breastcancer. In addition, antibody can be labeled or conjugated to enhanceits deleterious effect, e.g., with radionuclides and other energyemitting entitities, toxins, such as ricin, exotoxin A (ETA), anddiphtheria, cytotoxic or cytostatic agents, immunomodulators,chemotherapeutic agents, etc. See, e.g., U.S. Pat. No. 6,107,090.

[0119] An antibody or other specific-binding partner can be conjugatedto a second molecule, such as a cytotoxic agent, and used for targetingthe second molecule to a tissue-antigen positive cell (Vitetta, E. S. etal., 1993, Immunotoxin therapy, in DeVita, Jr., V. T. et al., eds,Cancer: Principles and Practice of Oncology, 4th ed., J. B. LippincottCo., Philadelphia, 2624-2636). Examples of cytotoxic agents include, butare not limited to, antimetabolites, alkylating agents, anthracyclines,antibiotics, anti-mitotic agents, radioisotopes and chemotherapeuticagents. Further examples of cytotoxic agents include, but are notlimited to ricin, doxorubicin, daunorubicin, taxol, ethidium bromide,mitomycin, etoposide, tenoposide, vincristine, vinblastine, colchicine,dihydroxy anthracin dione, actinomycin D, 1-dehydrotestosterone,diptheria toxin, Pseudomonas exotoxin (PE) A, PE40, abrin, elongationfactor-2 and glucocorticoid. Techniques for conjugating therapeuticagents to antibodies are well.

[0120] In addition to immunotherapy, polynucleotides and polypeptidescan be used as targets for non-immunotherapeutic applications, e.g.,using compounds which interfere with function, expression (e.g.,antisense as a therapeutic agent), assembly, etc. RNA interference canbe used in vivtro and in vivo to silence Human TARPP when its expressioncontributes to a disease (but also for other purposes, e.g., to identifythe gene's function to change a developmental pathway of a cell, etc.).See, e.g., Sharp and Zamore, Science, 287:2431-2433, 2001; Grishok etal., Science, 287:2494, 2001.

[0121] Delivery of therapeutic agents can be achieved according to anyeffective method, including, liposomes, viruses, plasmid vectors,bacterial delivery systems, orally, systemically, etc. Therapeuticagents of the present invention can be administered in any form by anyeffective route, including, e.g., oral, parenteral, enteral,intraperitoneal, topical, transdermal (e.g., using any standard patch),ophthalmic, nasally, local, non-oral, such as aerosal, inhalation,subcutaneous, intramuscular, buccal, sublingual, rectal, vaginal,intra-arterial, and intrathecal, etc. They can be administered alone, orin combination with any ingredient(s), active or inactive.

[0122] In addition to therapeutics, per se, the present invention alsorelates to methods of treating a disease of the immune or nervous systemshowing altered expression of human TARPP, comprising, e.g.,administering to a subject in need thereof a therapeutic agent which iseffective for regulating expression of said human TARPP and/or which iseffective in treating said disease. The term “treating” is usedconventionally, e.g., the management or care of a subject for thepurpose of combating, alleviating, reducing, relieving, improving thecondition of, etc., of a disease or disorder. Diseases or disorderswhich can be treated in accordance with the present invention include,but are not limited to autoimmune disease, such as multiple sclerosisand rheumatoid arthritis, and allergy. By the phrase “alteredexpression,” it is meant that the disease is associated with a mutationin the gene, or any modification to the gene (or corresponding product)which affects its normal function. Thus, expression of human TARPPrefers to, e.g., transcription, translation, splicing, stability of themRNA or protein product, activity of the gene product, differentialexpression, etc.

[0123] Any agent which “treats” the disease can be used. Such an agentcan be one which regulates the expression of the human TARPP. Expressionrefers to the same acts already mentioned, e.g. transcription,translation, splicing, stability of the mRNA or protein product,activity of the gene product, differential expression, etc. Forinstance, if the condition was a result of a complete deficiency of thegene product, administration of gene product to a patient would be saidto treat the disease and regulate the gene's expression. Many otherpossible situations are possible, e.g., where the gene is aberrantlyexpressed, and the therapeutic agent regulates the aberrant expressionby restoring its normal expression pattern.

[0124] Antisense

[0125] Antisense polynucleotide (e.g., RNA) can also be prepared from apolynucleotide according to the present invention, preferably ananti-sense to a sequence of SEQ ID NO 1, 3, 5, 7, 9, and others.Antisense polynucleotide can be used in various ways, such as toregulate or modulate expression of the polypeptides they encode, e.g.,inhibit their expression, for in situ hybridization, for therapeuticpurposes, for making targeted mutations (in vivo, triplex, etc.) etc.For guidance on administering and designing anti-sense, see, e.g., U.S.Pat. Nos. 6,200,960, 6,200,807, 6,197,584, 6,190,869, 6,190,661,6,187,587, 6,168,950, 6,153,595, 6,150,162, 6,133,246, 6,117,847,6,096,722, 6,087,343, 6,040,296, 6,005,095, 5,998,383, 5,994,230,5,891,725, 5,885,970, and 5,840,708. An antisense polynucleotides can beoperably linked to an expression control sequence. A total length ofabout 35 bp can be used in cell culture with cationic liposomes tofacilitate cellular uptake, but for in vivo use, preferably shorteroligonucleotides are administered, e.g. 25 nucleotides.

[0126] Antisense polynucleotides can comprise modified,nonnaturally-occurring nucleotides and linkages between the nucleotides(e.g., modification of the phosphate-sugar backbone; methyl phosphonate,phosphorothioate, or phosphorodithioate linkages; and 2′-O-methyl ribosesugar units), e.g., to enhance in vivo or in vitro stability, to confernuclease resistance, to modulate uptake, to modulate cellulardistribution and compartmentalization, etc. Any effective nucleotide ormodification can be used, including those already mentioned, as known inthe art, etc., e.g., disclosed in U.S. Pat. Nos. 6,133,438; 6,127,533;6,124,445; 6,121,437; 5,218,103 (e.g., nucleoside thiophosphoramidites);4,973,679; Sproat et al., “2′-O-Methyloligoribonucleotides: synthesisand applications,” Oligonucleotides and Analogs A Practical Approach,Eckstein (ed.), IRL Press, Oxford, 1991, 49-86; Iribarren et al.,“2′-O-Alkyl Oligoribonucleotides as Antisense Probes,” Proc. Natl. Acad.Sci. USA, 1990, 87, 7747-7751; Cotton et al., “2′-O-methyl, 2′-O-ethyloligoribonucleotides and phosphorothioate oligodeoxyribonucleotides asinhibitors of the in vitro U7 snRNP-dependent mRNA processing event,”Nucl. Acids Res., 1991, 19, 2629-2635.

[0127] Arrays

[0128] The present invention also relates to an ordered array ofpolynucleotide probes and specific-binding partners (e.g., antibodies)for detecting the expression of human TARPP in a sample, comprising, oneor more polynucleotide probes or specific binding partners associatedwith a solid support, wherein each probe is specific for human TARPP,and the probes comprise a nucleotide sequence of SEQ ID NO 1, 3, 5, 7,9, and others which is specific for said gene, a nucleotide sequencehaving sequence identity to SEQ ID NO 1, 3, 5, 7, 9, and others which isspecific for said gene or polynucleotide, or complements thereto, or aspecific-binding partner which is specific for human TARPP.

[0129] The phrase “ordered array” indicates that the probes are arrangedin an identifiable or position-addressable pattern, e.g., such as thearrays disclosed in U.S. Pat. Nos. 6,156,501, 6,077,673, 6,054,270,5,723,320, 5,700,637, WO09919711, WO00023803. The probes are associatedwith the solid support in any effective way. For instance, the probescan be bound to the solid support, either by polymerizing the probes onthe substrate, or by attaching a probe to the substrate. Association canbe, covalent, electrostatic, noncovalent, hydrophobic, hydrophilic,noncovalent, coordination, adsorbed, absorbed, polar, etc. When fibersor hollow filaments are utilized for the array, the probes can fill thehollow orifice, be absorbed into the solid filament, be attached to thesurface of the orifice, etc. Probes can be of any effective size,sequence identity, composition, etc., as already discussed.

[0130] Ordered arrays can further comprise polynucleotide probes orspecific-binding partners which are specific for other genes, includinggenes specific for immune or nervous tissues, or genes associated withdiseases thereof.

[0131] Transgenic Animals

[0132] The present invention also relates to transgenic animalscomprising human TARPP genes. Such genes, as discussed in more detailbelow, include, but are not limited to, functionally-disrupted genes,mutated genes, ectopically or selectively-expressed genes, inducible orregulatable genes, etc. These transgenic animals can be producedaccording to any suitable technique or method, including homologousrecombination, mutagenesis (e.g., ENU, Rathkolb et al., Exp. Physiol.,85(6):635-644, 2000), and the tetracycline-regulated gene expressionsystem (e.g., U.S. Pat. No. 6,242,667). The term “gene” as used hereinincludes any part of a gene, i.e., regulatory sequences, promoters,enhancers, exons, introns, coding sequences, etc. A human TARPP nucleicacid present in the construct or transgene can be naturally-occurringwild-type, polymorphic, or mutated.

[0133] Along these lines, polynucleotides of the present invention canbe used to create transgenic animals, e.g. a non-human animal,comprising at least one cell whose genome comprises a functionaldisruption of human TARPP. By the phrases “functional disruption” or“functionally disrupted,” it is meant that the gene does not express abiologically-active product. It can be substantially deficient in atleast one functional activity coded for by the gene. Expression of apolypeptide can be substantially absent, i.e., essentially undetectableamounts are made. However, polypeptide can also be made, but which isdeficient in activity, e.g., where only an amino-terminal portion of thegene product is produced. For example, the gene can be disrupted in aspecific region, e.g., in the sequence coding for amino acids 1-161 of ahuman TARPP. Cells and/or animals can also have targeted deletions,e.g., deletion of a coding sequence for amino acids 267-300 and/or312-331 of a human TARPP of SEQ ID NO 1 or 2.

[0134] The transgenic animal can comprise one or more cells. Whensubstantially all its cells contain the engineered gene, it can bereferred to as a transgenic animal “whose genome comprises” theengineered gene. This indicates that the endogenous gene loci of theanimal has been modified and substantially all cells contain suchmodification.

[0135] Functional disruption of the gene can be accomplished in anyeffective way, including, e.g., introduction of a stop codon into anypart of the coding sequence such that the resulting polypeptide isbiologically inactive (e.g., because it lacks a catalytic domain, aligand binding domain, etc.), introduction of a mutation into a promoteror other regulatory sequence that is effective to turn it off, or reducetranscription of the gene, insertion of an exogenous sequence into thegene which inactivates it (e.g., which disrupts the production of abiologically-active polypeptide or which disrupts the promoter or othertranscriptional machinery), deletion of sequences from the Human TARPPgene, etc. Examples of transgenic animals having functionally disruptedgenes are well known, e.g., as described in U.S. Pat. Nos. 6,239,326,6,225,525, 6,207,878, 6,194,633, 6,187,992, 6,180,849, 6,177,610,6,100,445, 6,087,555, 6,080,910, 6,069,297, 6,060,642, 6,028,244,6,013,858, 5,981,830, 5,866,760, 5,859,314, 5,850,004, 5,817,912,5,789,654, 5,777,195, and 5,569,824. A transgenic animal which comprisesthe functional disruption can also be referred to as a “knock-out”animal, since the biological activity of its human TARPP genes has been“knocked-out.” One or more the different splice forms, Br137A-E can alsobe knocked-out or disrupted, e.g., in cells or whole mammals. Knock-outcells and animals can be homozygous or heterozygous.

[0136] For creating functional disrupted genes, and other genemutations, homologous recombination technology is of special interestsince it allows specific regions of the genome to be targeted. Usinghomologous recombination methods, genes can be specifically-inactivated,specific mutations can be introduced, and exogenous sequences can beintroduced at specific sites. These methods are well known in the art,e.g., as described in the patents above. See, also, Robertson, Biol.Reproduc., 44(2):238-245, 1991. Generally, the genetic engineering isperformed in an embryonic stem (ES) cell, or other pluripotent cell line(e.g., adult stem cells, EG cells), and that genetically-modified cell(or nucleus) is used to create a whole organism. Nuclear transfer can beused in combination with homologous recombination technologies.

[0137] For example, the human TARPP locus can be disrupted in ES cellsusing a positive-negative selection method (e.g., Mansour et al.,Nature, 336:348-352, 1988). In this method, a targeting vector can beconstructed which comprises a part of the gene to be targeted. Aselectable marker, such as neomycin resistance genes, can be insertedinto a human TARPP exon present in the targeting vector, disrupting it.When the vector recombines with the ES cell genome, it disrupts thefunction of the gene. The presence in the cell of the vector can bedetermined by expression of neomycin resistance. See, e.g., U.S. Pat.No. 6,239,326. Cells having at least one functionally disrupted gene canbe used to make chimeric and germline animals, e.g., animals havingsomatic and/or germ cells comprising the engineered gene. Homozygousknock-out animals can be obtained from breeding heterozygous knock-outanimals. See, e.g., U.S. Pat. No. 6,225,525.

[0138] A transgenic animal, or animal cell, lacking one or morefunctional human TARPP genes (and lacking one or more functional copiesof the splice variant) can be useful in a variety of applications,including, as an animal model for diseases of the immune or nervoussystem, for drug screening assays (e.g., for DNA-binding activitiesother than those contributed by human TARPP; by making a cell deficientin one or more splice forms of human TARPP, the contribution of otherDNA binding activity can be specifically examined), as a source oftissues deficient in human TARPP activity, and any of the utilitiesmentioned in any issued U.S. Patent on transgenic animals, including,U.S. Pat. Nos. 6,239,326, 6,225,525, 6,207,878, 6,194,633, 6,187,992,6,180,849, 6,177,610, 6,100,445, 6,087,555, 6,080,910, 6,069,297,6,060,642, 6,028,244, 6,013,858, 5,981,830, 5,866,760, 5,859,314,5,850,004, 5,817,912, 5,789,654, 5,777,195, and 5,569,824. Theindividual contributions of the different forms of human TARPP can beassessed by disrupting specific regions of it.

[0139] A recombinant human TARPP nucleic acid refers to a gene which hasbeen introduced into a target host cell and optionally modified, such ascells derived from animals, plants, bacteria, yeast, etc. A recombinanthuman TARPP includes completely synthetic nucleic acid sequences,semi-synthetic nucleic acid sequences, sequences derived from naturalsources, and chimeras thereof. “Operable linkage” has the meaning usedthrough the specification, i.e., placed in a functional relationshipwith another nucleic acid. When a gene is operably linked to anexpression control sequence, as explained above, it indicates that thegene (e.g., coding sequence) is joined to the expression controlsequence (e.g., promoter) in such a way that facilitates transcriptionand translation of the coding sequence. As described above, the phrase“genome” indicates that the genome of the cell has been modified. Inthis case, the recombinant human TARPP has been stably integrated intothe genome of the animal. The human TARPP nucleic acid in operablelinkage with the expression control sequence can also be referred to asa construct or transgene.

[0140] Any expression control sequence can be used depending on thepurpose. For instance, if selective expression is desired, thenexpression control sequences which limit its expression can be selected.These include, e.g., tissue or cell-specific promoters, introns,enhancers, etc. For various methods of cell and tissue-specificexpression, see, e.g., U.S. Pat. Nos. 6,215,040, 6,210,736, and6,153,427. These also include the endogenous promoter, i.e., the codingsequence can be operably linked to its own promoter. Inducible andregulatable promoters can also be utilized.

[0141] The present invention also relates to a transgenic animal whichcontains a functionally disrupted and a transgene stably integrated intothe animals genome. Such an animal can be constructed using combinationsany of the above- and below-mentioned methods. Such animals have any ofthe aforementioned uses, including permitting the knock-out of thenormal gene and its replacement with a mutated gene. Such a transgenecan be integrated at the endogenous gene locus so that the functionaldisruption and “knock-in” are carried out in the same step.

[0142] In addition to the methods mentioned above, transgenic animalscan be prepared according to known methods, including, e.g., bypronuclear injection of recombinant genes into pronuclei of 1-cellembryos, incorporating an artificial yeast chromosome into embryonicstem cells, gene targeting methods, embryonic stem cell methodology,cloning methods, nuclear transfer methods. See, also, e.g., U.S. Pat.Nos. 4,736,866; 4,873,191; 4,873,316; 5,082,779; 5,304,489; 5,174,986;5,175,384; 5,175,385; 5,221,778; Gordon et al., Proc. Natl. Acad. Sci.,77:7380-7384, 1980; Palmiter et al., Cell, 41:343-345, 1985; Palmiter etal., Ann. Rev. Genet., 20:465-499, 1986; Askew et al., Mol. Cell. Bio.,13:4115-4124, 1993; Games et al. Nature, 373:523-527, 1995; Valanciusand Smithies, Mol. Cell. Bio., 11: 1402-1408, 1991; Stacey et al., Mol.Cell. Bio., 14:1009-1016, 1994; Hasty et al., Nature, 350:243-246, 1995;Rubinstein et al., Nucl. Acid Res., 21:2613-2617,1993; Cibelli et al.,Science, 280:1256-1258, 1998. For guidance on recombinase excisionsystems, see, e.g., U.S. Pat. Nos. 5,626,159, 5,527,695, and 5,434,066.See also, Orban, P. C., et al., “Tissue-and Site-Specific DNARecombination in Transgenic Mice,” Proc. Natl. Acad. Sci. USA,89:6861-6865 (1992); O'Gorman, S., et al., “Recombinase-Mediated GeneActivation and Site-Specific Integration in Mammalian Cells,” Science,251:1351-1355 (1991); Sauer, B., et al., “Cre-stimulated recombinationat loxP-Containing DNA sequences placed into the mammalian genome,”Polynucleotides Research, 17(1):147-161 (1989); Gagneten, S. et al.(1997) Nucl. Acids Res. 25:3326-3331; Xiao and Weaver (1997) Nucl. AcidsRes. 25:2985-2991; Agah, R. et al. (1997) J. Clin. Invest. 100: 169-179;Barlow, C. et al. (1997) Nucl. Acids Res. 25:2543-2545; Araki, K. et al.(1997) Nucl. Acids Res. 25:868-872; Mortensen, R. N. et al. (1992) Mol.Cell. Biol. 12:2391-2395 (G418 escalation method); Lakhlani, P. P. etal. (1997) Proc. Natl. Acad. Sci. USA 94:9950-9955 (“hit and run”);Westphal and Leder (1997) Curr. Biol. 7:530-533 (transposon-generated“knock-out” and “knock-in”); Templeton, N. S. et al. (1997) Gene Ther.4:700-709 (methods for efficient gene targeting, allowing for a highfrequency of homologous recombination events, e.g., without selectablemarkers); PCT International Publication WO 93/22443(functionally-disrupted).

[0143] A polynucleotide according to the present invention can beintroduced into any non-human animal, including a non-human mammal,mouse (Hogan et al., Manipulating the Mouse Embryo: A Laboratory Manual,Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, 1986), pig(Hammer et al., Nature, 315:343-345, 1985), sheep (Hammer et al.,Nature, 315:343-345, 1985), cattle, rat, or primate. See also, e.g.,Church, 1987, Trends in Biotech. 5:13-19; Clark et al., Trends inBiotech. 5:20-24, 1987); and DePamphilis et al., BioTechniques,6:662-680, 1988. Transgenic animals can be produced by the methodsdescribed in U.S. Pat. No. 5,994,618, and utilized for any of theutilities described therein.

[0144] Database

[0145] The present invention also relates to electronic forms ofpolynucleotides, polypeptides, etc., of the present invention, includingcomputer-readable medium (e.g., magnetic, optical, etc., stored in anysuitable format, such as flat files or hierarchical files) whichcomprise such sequences, or fragments thereof, e-commerce-related means,etc. Along these lines, the present invention relates to methods ofretrieving gene sequences from a computer-readable medium, comprising,one or more of the following steps in any effective order, e.g.,selecting a cell or gene expression profile, e.g., a profile thatspecifies that said gene is expressed in brain and/or immune cells, and,and retrieving said expressed gene sequences, where the gene sequencesconsist of the genes represented by SEQ ID Nos 1-10

[0146] A “gene expression profile” means the list of tissues, cells,etc., in which a defined gene is expressed (i.e, transcribed and/ortranslated). A “cell expression profile” means the genes which areexpressed in the particular cell type. The profile can be a list of thetissues in which the gene is expressed, but can include additionalinformation as well, including level of expression (e.g., a quantity ascompared or normalized to a control gene), and information on temporal(e.g., at what point in the cell-cycle or developmental program) andspatial expression. By the phrase “selecting a gene or cell expressionprofile,” it is meant that a user decides what type of gene or cellexpression pattern he is interested in retrieving, e.g., he may requirethat the gene is differentially expressed in a tissue. Any pattern ofexpression preferences may be selected. The selecting can be performedby any effective method. In general, “selecting” refers to the processin which a user forms a query that is used to search a database of geneexpression profiles. The step of retrieving involves searching forresults in a database that correspond to the query set forth in theselecting step. Any suitable algorithm can be utilized to perform thesearch query, including algorithms that look for matches, or thatperform optimization between query and data. The database is informationthat has been stored in an appropriate storage medium, having a suitablecomputer-readable format. Once results are retrieved, they can bedisplayed in any suitable format, such as HTML. A query is formed by theuser to retrieve the set of genes from the database having the desiredgene or cell expression profile. Once the query is inputted into thesystem, a search algorithm is used to interrogate the database, andretrieve results.

[0147] Advertising, Licensing, etc., Methods

[0148] The present invention also relates to methods of advertising,licensing, selling, purchasing, brokering, etc., genes, polynucleotides,specific-binding partners, antibodies, etc., of the present invention.Methods can comprises, e.g., displaying a human TARPP gene, human TARPPpolypeptide, or antibody specific for human TARPP in a printed orcomputer-readable medium (e.g., on the Web or Internet), accepting anoffer to purchase said gene, polypeptide, or antibody.

[0149] Other

[0150] A polynucleotide, probe, polypeptide, antibody, specific-bindingpartner, etc., according to the present invention can be isolated. Theterm “isolated” means that the material is in a form in which it is notfound in its original environment or in nature, e.g., more concentrated,more purified, separated from component, etc. An isolated polynucleotideincludes, e.g., a polynucleotide having the sequenced separated from thechromosomal DNA found in a living animal, e.g., as the complete gene, atranscript, or a cDNA. This polynucleotide can be part of a vector orinserted into a chromosome (by specific gene-targeting or by randomintegration at a position other than its normal position) and still beisolated in that it is not in a form that is found in its naturalenvironment. A polynucleotide, polypeptide, etc., of the presentinvention can also be substantially purified. By substantially purified,it is meant that polynucleotide or polypeptide is separated and isessentially free from other polynucleotides or polypeptides, i.e., thepolynucleotide or polypeptide is the primary and active constituent. Apolynucleotide can also be a recombinant molecule. By “recombinant,” itis meant that the polynucleotide is an arrangement or form which doesnot occur in nature. For instance, a recombinant molecule comprising apromoter sequence would not encompass the naturally-occurring gene, butwould include the promoter operably linked to a coding sequence notassociated with it in nature, e.g., a reporter gene, or a truncation ofthe normal coding sequence.

[0151] The term “marker” is used herein to indicate a means fordetecting or labeling a target. A marker can be a polynucleotide(usually referred to as a “probe”), polypeptide (e.g., an antibodyconjugated to a detectable label), PNA, or any effective material.

[0152] The topic headings set forth above are meant as guidance wherecertain information can be found in the application, but are notintended to be the only source in the application where information onsuch topic can be found. Reference materials

[0153] For other aspects of the polynucleotides, reference is made tostandard textbooks of molecular biology. See, e.g., Hames et al.,Polynucleotide Hybridization, IL Press, 1985; Davis et al., BasicMethods in Molecular Biology, Elsevir Sciences Publishing, Inc., NewYork, 1986; Sambrook et al., Molecular Cloning, CSH Press, 1989; Howe,Gene Cloning and Manipulation, Cambridge University Press, 1995; Ausubelet al., Current Protocols in Molecular Biology, John Wiley & Sons, Inc.,1994-1998.

[0154] The preceding preferred specific embodiments are merelyillustrative, and not limiting the remainder of the disclosure in anyway whatsoever. The entire disclosure of all applications, patents andpublications, cited above and in the figures are hereby incorporated byreference in their entirety.

1 15 1 3369 DNA Homo sapiens CDS (250)..(2793) 1 gctggatcaa gctgtgaacgtgatttgctg gaagctggtt gacgatgtgt cacactgtgt 60 aagggaatcg catggagatgggcattccga actgttaatg gggacatggg actccagttg 120 tctctgatca cttgtgtggattttcctggc gtagaacgac agaagccgct agtaagtcgc 180 caagacctac agcaggaattctgcaccaaa gggcataaaa tcttgttatt ttaatttgca 240 tctgggaga atg tct gagcaa gga gac ctg aat cag gca ata gca gag gaa 291 Met Ser Glu Gln Gly AspLeu Asn Gln Ala Ile Ala Glu Glu 1 5 10 gga ggg act gag cag gag acg gccact cca gag aac ggc att gtt aaa 339 Gly Gly Thr Glu Gln Glu Thr Ala ThrPro Glu Asn Gly Ile Val Lys 15 20 25 30 tca gaa agt ctg gat gaa gag gagaaa ctg gaa ctg cag agg cgg ctg 387 Ser Glu Ser Leu Asp Glu Glu Glu LysLeu Glu Leu Gln Arg Arg Leu 35 40 45 gag gct cag aat caa gaa aga aga aaatcc aag tca gga gca gga aaa 435 Glu Ala Gln Asn Gln Glu Arg Arg Lys SerLys Ser Gly Ala Gly Lys 50 55 60 ggt aaa ctg act cgc agt ctt gct gtc tgtgag gaa tct tct gcc aga 483 Gly Lys Leu Thr Arg Ser Leu Ala Val Cys GluGlu Ser Ser Ala Arg 65 70 75 cca gga ggt gaa agt ctt cag gat cag gaa tcaatt cat tta cag ctt 531 Pro Gly Gly Glu Ser Leu Gln Asp Gln Glu Ser IleHis Leu Gln Leu 80 85 90 tcc agt ttt tcc agc ctg caa gag gag gat aaa tctagg aaa gat gac 579 Ser Ser Phe Ser Ser Leu Gln Glu Glu Asp Lys Ser ArgLys Asp Asp 95 100 105 110 tct gaa aga gaa aaa gaa aag gat aaa aac aaagat aaa acc tct gaa 627 Ser Glu Arg Glu Lys Glu Lys Asp Lys Asn Lys AspLys Thr Ser Glu 115 120 125 aaa ccc aag atc aga atg tta tca aaa gat tgcagc caa gaa tac acg 675 Lys Pro Lys Ile Arg Met Leu Ser Lys Asp Cys SerGln Glu Tyr Thr 130 135 140 gat tct aca ggc ata gac tta cac gag ttt ctgatt aac aca tta aag 723 Asp Ser Thr Gly Ile Asp Leu His Glu Phe Leu IleAsn Thr Leu Lys 145 150 155 aat aat tcc agg gac agg atg ata ctt ttg aaaatg gag cag gaa att 771 Asn Asn Ser Arg Asp Arg Met Ile Leu Leu Lys MetGlu Gln Glu Ile 160 165 170 att gat ttc att gct gac aac aat aat cat tataaa aag ttc cct cag 819 Ile Asp Phe Ile Ala Asp Asn Asn Asn His Tyr LysLys Phe Pro Gln 175 180 185 190 atg tca tcg tat cag agg atg ctt gtc catcga gtg gca gct tat ttt 867 Met Ser Ser Tyr Gln Arg Met Leu Val His ArgVal Ala Ala Tyr Phe 195 200 205 gga ttg gat cac aat gtg gat caa aca ggaaaa tct gtt atc atc aac 915 Gly Leu Asp His Asn Val Asp Gln Thr Gly LysSer Val Ile Ile Asn 210 215 220 aag acc agc agc acc aga ata cca gag caaagg ttt tgt gaa cat tta 963 Lys Thr Ser Ser Thr Arg Ile Pro Glu Gln ArgPhe Cys Glu His Leu 225 230 235 aaa gat gaa aaa ggt gaa gaa tcc cag aagcgg ttt atc ttg aag cga 1011 Lys Asp Glu Lys Gly Glu Glu Ser Gln Lys ArgPhe Ile Leu Lys Arg 240 245 250 gat aac tct agt att gat aaa gaa gac aatcag caa aac aga atg cat 1059 Asp Asn Ser Ser Ile Asp Lys Glu Asp Asn GlnGln Asn Arg Met His 255 260 265 270 cca ttt aga gat gac aga cga agt aaatca att gaa gag aga gaa gag 1107 Pro Phe Arg Asp Asp Arg Arg Ser Lys SerIle Glu Glu Arg Glu Glu 275 280 285 gaa tat cag aga gtg agg gag aga atattt gca cac gat tca gtt tgc 1155 Glu Tyr Gln Arg Val Arg Glu Arg Ile PheAla His Asp Ser Val Cys 290 295 300 tcc cag gaa agc ctt ttt gtg gaa aacagt agg ctc ttg gaa gac agt 1203 Ser Gln Glu Ser Leu Phe Val Glu Asn SerArg Leu Leu Glu Asp Ser 305 310 315 aac ata tgc aat gag acc tat aag aaaaga cag ctc ttt cgg ggc aac 1251 Asn Ile Cys Asn Glu Thr Tyr Lys Lys ArgGln Leu Phe Arg Gly Asn 320 325 330 aga gat ggc tca ggg aga aca tct gggagt cga cag agc agc tca gaa 1299 Arg Asp Gly Ser Gly Arg Thr Ser Gly SerArg Gln Ser Ser Ser Glu 335 340 345 350 aat gaa ctc aag tgg tct gac caccaa agg gcc tgg agc agc aca gac 1347 Asn Glu Leu Lys Trp Ser Asp His GlnArg Ala Trp Ser Ser Thr Asp 355 360 365 tcc gac agt tcc aac cgc aat ctaaag ccc gcc atg acc aag acg gcg 1395 Ser Asp Ser Ser Asn Arg Asn Leu LysPro Ala Met Thr Lys Thr Ala 370 375 380 agt ttt ggg ggc atc acg gtg ctgacc agg ggt gac agc act tcc agt 1443 Ser Phe Gly Gly Ile Thr Val Leu ThrArg Gly Asp Ser Thr Ser Ser 385 390 395 act agg agt acc ggg aag ctg tccaaa gca ggt tcc gag tct tcc agc 1491 Thr Arg Ser Thr Gly Lys Leu Ser LysAla Gly Ser Glu Ser Ser Ser 400 405 410 agt gca ggc tcc tca gga tcg ctgtcc cgc acc cat cca cct ctc cag 1539 Ser Ala Gly Ser Ser Gly Ser Leu SerArg Thr His Pro Pro Leu Gln 415 420 425 430 agc aca ccc cta gtc tca ggtgtg gca gct ggc tct cca ggc tgt gtg 1587 Ser Thr Pro Leu Val Ser Gly ValAla Ala Gly Ser Pro Gly Cys Val 435 440 445 cct tat cca gag aat gga ataggg ggc cag gtt gct ccc agc agc acc 1635 Pro Tyr Pro Glu Asn Gly Ile GlyGly Gln Val Ala Pro Ser Ser Thr 450 455 460 agc tac atc ctc ctt cca cttgaa gct gca aca ggc atc ccg cct gga 1683 Ser Tyr Ile Leu Leu Pro Leu GluAla Ala Thr Gly Ile Pro Pro Gly 465 470 475 agc atc ctt ctt aat cca cacaca ggc cag ccc ttt gtg aat ccc gat 1731 Ser Ile Leu Leu Asn Pro His ThrGly Gln Pro Phe Val Asn Pro Asp 480 485 490 gga act cct gca ata tac aaccca ccc acc agt cag cag ccc ctg cga 1779 Gly Thr Pro Ala Ile Tyr Asn ProPro Thr Ser Gln Gln Pro Leu Arg 495 500 505 510 agc gcc atg gtg ggg cagtcc caa cag cag cca cca cag cag cag ccc 1827 Ser Ala Met Val Gly Gln SerGln Gln Gln Pro Pro Gln Gln Gln Pro 515 520 525 tcc ccg cag ccc caa cagcag gtc cag cca ccg cag cca cag atg gca 1875 Ser Pro Gln Pro Gln Gln GlnVal Gln Pro Pro Gln Pro Gln Met Ala 530 535 540 ggc cct ctg gtc act cagtct gtc cag ggg ctg cag gct tcc tcc cag 1923 Gly Pro Leu Val Thr Gln SerVal Gln Gly Leu Gln Ala Ser Ser Gln 545 550 555 tca gtg caa tat cca gcagtc tct ttt cct ccc cag cac ctc cta cct 1971 Ser Val Gln Tyr Pro Ala ValSer Phe Pro Pro Gln His Leu Leu Pro 560 565 570 gtg tct cca acg cag cacttt ccc atg aga gat gat gtg gca aca cag 2019 Val Ser Pro Thr Gln His PhePro Met Arg Asp Asp Val Ala Thr Gln 575 580 585 590 ttt ggc cag atg accctg agc cgg cag tcc tcg ggg gag act cct gaa 2067 Phe Gly Gln Met Thr LeuSer Arg Gln Ser Ser Gly Glu Thr Pro Glu 595 600 605 ccc cca tca ggt cctgtc tac cca tcc tcc ctt atg cca cag ccg gcc 2115 Pro Pro Ser Gly Pro ValTyr Pro Ser Ser Leu Met Pro Gln Pro Ala 610 615 620 cag cag ccc agc tatgta atc gcc tct aca ggc cag cag ctt cct aca 2163 Gln Gln Pro Ser Tyr ValIle Ala Ser Thr Gly Gln Gln Leu Pro Thr 625 630 635 gga gga ttc tca ggctct ggc cct ccc atc tcc cag cag gtc ctc cag 2211 Gly Gly Phe Ser Gly SerGly Pro Pro Ile Ser Gln Gln Val Leu Gln 640 645 650 ccc cct ccc tca ccacag gga ttt gtg caa cag cct ccg cct gca cag 2259 Pro Pro Pro Ser Pro GlnGly Phe Val Gln Gln Pro Pro Pro Ala Gln 655 660 665 670 atg cct gta tattat tac cca tct ggt cag tac cct acc tca acc acg 2307 Met Pro Val Tyr TyrTyr Pro Ser Gly Gln Tyr Pro Thr Ser Thr Thr 675 680 685 caa cag tac cggccc atg gcc ccg gtt cag tac aac gct cag agg agt 2355 Gln Gln Tyr Arg ProMet Ala Pro Val Gln Tyr Asn Ala Gln Arg Ser 690 695 700 caa cag atg ccacag gca gca cag caa gca ggt tac cag cca gtc ttg 2403 Gln Gln Met Pro GlnAla Ala Gln Gln Ala Gly Tyr Gln Pro Val Leu 705 710 715 tct ggt caa caggga ttc caa ggc cta ata gga gtg cag cag cca cct 2451 Ser Gly Gln Gln GlyPhe Gln Gly Leu Ile Gly Val Gln Gln Pro Pro 720 725 730 cag agt cag aacgtg ata aat aac caa caa gga act ccg gtg caa agc 2499 Gln Ser Gln Asn ValIle Asn Asn Gln Gln Gly Thr Pro Val Gln Ser 735 740 745 750 gtg atg gtttcc tac cca aca atg tct tct tat cag gtg cca atg acc 2547 Val Met Val SerTyr Pro Thr Met Ser Ser Tyr Gln Val Pro Met Thr 755 760 765 cag ggt tctcaa gga ctg ccc cag cag tca tac caa cag cca atc atg 2595 Gln Gly Ser GlnGly Leu Pro Gln Gln Ser Tyr Gln Gln Pro Ile Met 770 775 780 cta cct aaccag gca ggt caa ggg tca ctc cca gcc act gga atg cct 2643 Leu Pro Asn GlnAla Gly Gln Gly Ser Leu Pro Ala Thr Gly Met Pro 785 790 795 gtt tac tgtaat gtc aca ccg ccc acc cct cag aac aac ctt agg ctg 2691 Val Tyr Cys AsnVal Thr Pro Pro Thr Pro Gln Asn Asn Leu Arg Leu 800 805 810 att ggc ccacac tgc ccc tcc agc act gtc cca gtg atg tca gct agc 2739 Ile Gly Pro HisCys Pro Ser Ser Thr Val Pro Val Met Ser Ala Ser 815 820 825 830 tgc agaaca aac tgt gca agt atg agc aat gct ggt tgg cag gtc aaa 2787 Cys Arg ThrAsn Cys Ala Ser Met Ser Asn Ala Gly Trp Gln Val Lys 835 840 845 ttc tgagagctctggc tgtggtacat ttcttcagat atttctcatg gcctttgatg 2843 Phegaagaggaac aaggtgggaa aactggctga ggacttaagt attcactcaa cactcaaatg 2903attgctgctg gtattctgta aaaaataaac aaagactaat atacacgtta gctggttaat 2963ggtgcatatt tctgtcatgt ctgctaggta tgcctttata gcttagctag tgacatgaat 3023tcatcaaggt aagattttct cctaccactg aataccactg tgtagattat aatatcccta 3083atttggatta gttttgtact ttgtgttgag tttgtgatgc taaaagtatt taaaaattat 3143atactaaatc acattgtacc aaagctgtaa tggaaaagca aagaagaatt gatgaattga 3203aggaataatt tatatacatt atagagtttt cttttttaat ggatatatac tgtattgtag 3263tgtttaatca aaataaaact atttgacctt atggaggaag gtcatgtttt taccaccaaa 3323aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaa 3369 2 847 PRT Homosapiens 2 Met Ser Glu Gln Gly Asp Leu Asn Gln Ala Ile Ala Glu Glu GlyGly 1 5 10 15 Thr Glu Gln Glu Thr Ala Thr Pro Glu Asn Gly Ile Val LysSer Glu 20 25 30 Ser Leu Asp Glu Glu Glu Lys Leu Glu Leu Gln Arg Arg LeuGlu Ala 35 40 45 Gln Asn Gln Glu Arg Arg Lys Ser Lys Ser Gly Ala Gly LysGly Lys 50 55 60 Leu Thr Arg Ser Leu Ala Val Cys Glu Glu Ser Ser Ala ArgPro Gly 65 70 75 80 Gly Glu Ser Leu Gln Asp Gln Glu Ser Ile His Leu GlnLeu Ser Ser 85 90 95 Phe Ser Ser Leu Gln Glu Glu Asp Lys Ser Arg Lys AspAsp Ser Glu 100 105 110 Arg Glu Lys Glu Lys Asp Lys Asn Lys Asp Lys ThrSer Glu Lys Pro 115 120 125 Lys Ile Arg Met Leu Ser Lys Asp Cys Ser GlnGlu Tyr Thr Asp Ser 130 135 140 Thr Gly Ile Asp Leu His Glu Phe Leu IleAsn Thr Leu Lys Asn Asn 145 150 155 160 Ser Arg Asp Arg Met Ile Leu LeuLys Met Glu Gln Glu Ile Ile Asp 165 170 175 Phe Ile Ala Asp Asn Asn AsnHis Tyr Lys Lys Phe Pro Gln Met Ser 180 185 190 Ser Tyr Gln Arg Met LeuVal His Arg Val Ala Ala Tyr Phe Gly Leu 195 200 205 Asp His Asn Val AspGln Thr Gly Lys Ser Val Ile Ile Asn Lys Thr 210 215 220 Ser Ser Thr ArgIle Pro Glu Gln Arg Phe Cys Glu His Leu Lys Asp 225 230 235 240 Glu LysGly Glu Glu Ser Gln Lys Arg Phe Ile Leu Lys Arg Asp Asn 245 250 255 SerSer Ile Asp Lys Glu Asp Asn Gln Gln Asn Arg Met His Pro Phe 260 265 270Arg Asp Asp Arg Arg Ser Lys Ser Ile Glu Glu Arg Glu Glu Glu Tyr 275 280285 Gln Arg Val Arg Glu Arg Ile Phe Ala His Asp Ser Val Cys Ser Gln 290295 300 Glu Ser Leu Phe Val Glu Asn Ser Arg Leu Leu Glu Asp Ser Asn Ile305 310 315 320 Cys Asn Glu Thr Tyr Lys Lys Arg Gln Leu Phe Arg Gly AsnArg Asp 325 330 335 Gly Ser Gly Arg Thr Ser Gly Ser Arg Gln Ser Ser SerGlu Asn Glu 340 345 350 Leu Lys Trp Ser Asp His Gln Arg Ala Trp Ser SerThr Asp Ser Asp 355 360 365 Ser Ser Asn Arg Asn Leu Lys Pro Ala Met ThrLys Thr Ala Ser Phe 370 375 380 Gly Gly Ile Thr Val Leu Thr Arg Gly AspSer Thr Ser Ser Thr Arg 385 390 395 400 Ser Thr Gly Lys Leu Ser Lys AlaGly Ser Glu Ser Ser Ser Ser Ala 405 410 415 Gly Ser Ser Gly Ser Leu SerArg Thr His Pro Pro Leu Gln Ser Thr 420 425 430 Pro Leu Val Ser Gly ValAla Ala Gly Ser Pro Gly Cys Val Pro Tyr 435 440 445 Pro Glu Asn Gly IleGly Gly Gln Val Ala Pro Ser Ser Thr Ser Tyr 450 455 460 Ile Leu Leu ProLeu Glu Ala Ala Thr Gly Ile Pro Pro Gly Ser Ile 465 470 475 480 Leu LeuAsn Pro His Thr Gly Gln Pro Phe Val Asn Pro Asp Gly Thr 485 490 495 ProAla Ile Tyr Asn Pro Pro Thr Ser Gln Gln Pro Leu Arg Ser Ala 500 505 510Met Val Gly Gln Ser Gln Gln Gln Pro Pro Gln Gln Gln Pro Ser Pro 515 520525 Gln Pro Gln Gln Gln Val Gln Pro Pro Gln Pro Gln Met Ala Gly Pro 530535 540 Leu Val Thr Gln Ser Val Gln Gly Leu Gln Ala Ser Ser Gln Ser Val545 550 555 560 Gln Tyr Pro Ala Val Ser Phe Pro Pro Gln His Leu Leu ProVal Ser 565 570 575 Pro Thr Gln His Phe Pro Met Arg Asp Asp Val Ala ThrGln Phe Gly 580 585 590 Gln Met Thr Leu Ser Arg Gln Ser Ser Gly Glu ThrPro Glu Pro Pro 595 600 605 Ser Gly Pro Val Tyr Pro Ser Ser Leu Met ProGln Pro Ala Gln Gln 610 615 620 Pro Ser Tyr Val Ile Ala Ser Thr Gly GlnGln Leu Pro Thr Gly Gly 625 630 635 640 Phe Ser Gly Ser Gly Pro Pro IleSer Gln Gln Val Leu Gln Pro Pro 645 650 655 Pro Ser Pro Gln Gly Phe ValGln Gln Pro Pro Pro Ala Gln Met Pro 660 665 670 Val Tyr Tyr Tyr Pro SerGly Gln Tyr Pro Thr Ser Thr Thr Gln Gln 675 680 685 Tyr Arg Pro Met AlaPro Val Gln Tyr Asn Ala Gln Arg Ser Gln Gln 690 695 700 Met Pro Gln AlaAla Gln Gln Ala Gly Tyr Gln Pro Val Leu Ser Gly 705 710 715 720 Gln GlnGly Phe Gln Gly Leu Ile Gly Val Gln Gln Pro Pro Gln Ser 725 730 735 GlnAsn Val Ile Asn Asn Gln Gln Gly Thr Pro Val Gln Ser Val Met 740 745 750Val Ser Tyr Pro Thr Met Ser Ser Tyr Gln Val Pro Met Thr Gln Gly 755 760765 Ser Gln Gly Leu Pro Gln Gln Ser Tyr Gln Gln Pro Ile Met Leu Pro 770775 780 Asn Gln Ala Gly Gln Gly Ser Leu Pro Ala Thr Gly Met Pro Val Tyr785 790 795 800 Cys Asn Val Thr Pro Pro Thr Pro Gln Asn Asn Leu Arg LeuIle Gly 805 810 815 Pro His Cys Pro Ser Ser Thr Val Pro Val Met Ser AlaSer Cys Arg 820 825 830 Thr Asn Cys Ala Ser Met Ser Asn Ala Gly Trp GlnVal Lys Phe 835 840 845 3 3374 DNA Homo sapiens CDS (329)..(2812) 3gtctattttt aatgctattt aatgaaggag cgagcgcctc actcagcaat aaaagaagca 60tgagggaaga cagagcagtg catggttatg gatactggac aaggatattt ggaaaggttg 120acgatgtgtc acactgtgta agggaatcgc atggagatgg gcattccgaa ctgttaatgg 180ggacatggga ctccagttgt ctctgatcac ttgtgtggat tttcctggcg tagaacgaca 240gaagccgcta gtaagtcgcc aagacctaca gcaggaattc tgcaccaaag ggcataaaat 300cttgttattt taatttgcat ctgggaga atg tct gag caa gga gac ctg aat 352 MetSer Glu Gln Gly Asp Leu Asn 1 5 cag gca ata gca gag gaa gga ggg act gagcag gag acg gcc act cca 400 Gln Ala Ile Ala Glu Glu Gly Gly Thr Glu GlnGlu Thr Ala Thr Pro 10 15 20 gag aac ggc att gtt aaa tca gaa agt ctg gatgaa gag gag aaa ctg 448 Glu Asn Gly Ile Val Lys Ser Glu Ser Leu Asp GluGlu Glu Lys Leu 25 30 35 40 gaa ctg cag agg cgg ctg gag gct cag aat caagaa aga aga aaa tcc 496 Glu Leu Gln Arg Arg Leu Glu Ala Gln Asn Gln GluArg Arg Lys Ser 45 50 55 aag tca gga gca gga aaa ggt aaa ctg act cgc agtctt gct gtc tgt 544 Lys Ser Gly Ala Gly Lys Gly Lys Leu Thr Arg Ser LeuAla Val Cys 60 65 70 gag gaa tct tct gcc aga cca gga ggt gaa agt ctt caggat cag gaa 592 Glu Glu Ser Ser Ala Arg Pro Gly Gly Glu Ser Leu Gln AspGln Glu 75 80 85 tca att cat tta cag ctt tcc agt ttt tcc agc ctg caa gaggag gat 640 Ser Ile His Leu Gln Leu Ser Ser Phe Ser Ser Leu Gln Glu GluAsp 90 95 100 aaa tct agg aaa gat gac tct gaa aga gaa aaa gaa aag gataaa aac 688 Lys Ser Arg Lys Asp Asp Ser Glu Arg Glu Lys Glu Lys Asp LysAsn 105 110 115 120 aaa gat aaa acc tct gaa aaa ccc aag atc aga atg ttatca aaa gat 736 Lys Asp Lys Thr Ser Glu Lys Pro Lys Ile Arg Met Leu SerLys Asp 125 130 135 tgc agc caa gaa tac acg gat tct aca ggc ata gac ttacac gag ttt 784 Cys Ser Gln Glu Tyr Thr Asp Ser Thr Gly Ile Asp Leu HisGlu Phe 140 145 150 ctg att aac aca tta aag aat aat tcc agg gac agg atgata ctt ttg 832 Leu Ile Asn Thr Leu Lys Asn Asn Ser Arg Asp Arg Met IleLeu Leu 155 160 165 aaa atg gag cag gaa att att gat ttc att gct gac aacaat aat cat 880 Lys Met Glu Gln Glu Ile Ile Asp Phe Ile Ala Asp Asn AsnAsn His 170 175 180 tat aaa aag ttc cct cag atg tca tcg tat cag agg atgctt gtc cat 928 Tyr Lys Lys Phe Pro Gln Met Ser Ser Tyr Gln Arg Met LeuVal His 185 190 195 200 cga gtg gca gct tat ttt gga ttg gat cac aat gtggat caa aca gga 976 Arg Val Ala Ala Tyr Phe Gly Leu Asp His Asn Val AspGln Thr Gly 205 210 215 aaa tct gtt atc atc aac aag acc agc agc acc agaata cca gag caa 1024 Lys Ser Val Ile Ile Asn Lys Thr Ser Ser Thr Arg IlePro Glu Gln 220 225 230 agg ttt tgt gaa cat tta aaa gat gaa aaa ggt gaagaa tcc cag aag 1072 Arg Phe Cys Glu His Leu Lys Asp Glu Lys Gly Glu GluSer Gln Lys 235 240 245 cgg ttt atc ttg aag cga gat aac tct agt att gataaa gaa gac aat 1120 Arg Phe Ile Leu Lys Arg Asp Asn Ser Ser Ile Asp LysGlu Asp Asn 250 255 260 cag caa aac aga atg cat cca ttt aga gat gac agacga agt aaa tca 1168 Gln Gln Asn Arg Met His Pro Phe Arg Asp Asp Arg ArgSer Lys Ser 265 270 275 280 att gaa gag aga gaa gag gaa tat cag aga gtgagg gag aga ata ttt 1216 Ile Glu Glu Arg Glu Glu Glu Tyr Gln Arg Val ArgGlu Arg Ile Phe 285 290 295 gca cac gat tca gtt tgc tcc cag gaa agc cttttt gtg gaa aac agg 1264 Ala His Asp Ser Val Cys Ser Gln Glu Ser Leu PheVal Glu Asn Arg 300 305 310 ggc aac aga gat ggc tca ggg aga aca tct gggagt cga cag agc agc 1312 Gly Asn Arg Asp Gly Ser Gly Arg Thr Ser Gly SerArg Gln Ser Ser 315 320 325 tca gaa aat gaa ctc aag tgg tct gac cac caaagg gcc tgg agc agc 1360 Ser Glu Asn Glu Leu Lys Trp Ser Asp His Gln ArgAla Trp Ser Ser 330 335 340 aca gac tcc gac agt tcc aac cgc aat cta aagccc gcc atg acc aag 1408 Thr Asp Ser Asp Ser Ser Asn Arg Asn Leu Lys ProAla Met Thr Lys 345 350 355 360 acg gcg agt ttt ggg ggc atc acg gtg ctgacc agg ggt gac agc act 1456 Thr Ala Ser Phe Gly Gly Ile Thr Val Leu ThrArg Gly Asp Ser Thr 365 370 375 tcc agt act agg agt acc ggg aag ctg tccaaa gca ggt tcc gag tct 1504 Ser Ser Thr Arg Ser Thr Gly Lys Leu Ser LysAla Gly Ser Glu Ser 380 385 390 tcc agc agt gca ggc tcc tca gga tcg ctgtcc cgc acc cat cca cct 1552 Ser Ser Ser Ala Gly Ser Ser Gly Ser Leu SerArg Thr His Pro Pro 395 400 405 ctc cag agc aca ccc cta gtc tca ggt gtggca gct ggc tct cca ggc 1600 Leu Gln Ser Thr Pro Leu Val Ser Gly Val AlaAla Gly Ser Pro Gly 410 415 420 tgt gtg cct tat cca gag aat gga ata gggggc cag gtt gct ccc agc 1648 Cys Val Pro Tyr Pro Glu Asn Gly Ile Gly GlyGln Val Ala Pro Ser 425 430 435 440 agc acc agc tac atc ctc ctt cca cttgaa gct gca aca ggc atc ccg 1696 Ser Thr Ser Tyr Ile Leu Leu Pro Leu GluAla Ala Thr Gly Ile Pro 445 450 455 cct gga agc atc ctt ctt aat cca cacaca ggc cag ccc ttt gtg aat 1744 Pro Gly Ser Ile Leu Leu Asn Pro His ThrGly Gln Pro Phe Val Asn 460 465 470 ccc gat gga act cct gca ata tac aaccca ccc acc agt cag cag ccc 1792 Pro Asp Gly Thr Pro Ala Ile Tyr Asn ProPro Thr Ser Gln Gln Pro 475 480 485 ctg cga agc gcc atg gtg ggg cag tcccaa cag cag ccg cca cag cag 1840 Leu Arg Ser Ala Met Val Gly Gln Ser GlnGln Gln Pro Pro Gln Gln 490 495 500 cag ccc tcc ccg cag ccc caa cag caggtc cag cca ccg cag cca cag 1888 Gln Pro Ser Pro Gln Pro Gln Gln Gln ValGln Pro Pro Gln Pro Gln 505 510 515 520 atg gca ggc cct ctg gtc act cagtct gtc cag ggg ctg cag gct tcc 1936 Met Ala Gly Pro Leu Val Thr Gln SerVal Gln Gly Leu Gln Ala Ser 525 530 535 tcc cag tca gtg caa tat ccg gcagtc tct ttt cct ccc cag cac ctc 1984 Ser Gln Ser Val Gln Tyr Pro Ala ValSer Phe Pro Pro Gln His Leu 540 545 550 cta cct gtg tct cca acg cag cacttt ccc atg aga gat gat gtg gca 2032 Leu Pro Val Ser Pro Thr Gln His PhePro Met Arg Asp Asp Val Ala 555 560 565 aca cag ttt ggc cag atg acc ctgagc cgg cag tcc tcg ggg gag act 2080 Thr Gln Phe Gly Gln Met Thr Leu SerArg Gln Ser Ser Gly Glu Thr 570 575 580 cct gaa ccc cca tca ggt cct gtctac cca tcc tcc ctt atg cca cag 2128 Pro Glu Pro Pro Ser Gly Pro Val TyrPro Ser Ser Leu Met Pro Gln 585 590 595 600 ccg gcc cag cag ccc agc tatgta atc gcc tct aca ggc cag cag ctt 2176 Pro Ala Gln Gln Pro Ser Tyr ValIle Ala Ser Thr Gly Gln Gln Leu 605 610 615 cct aca gga gga ttc tca ggctct ggc cct ccc atc tcc cag cag gtc 2224 Pro Thr Gly Gly Phe Ser Gly SerGly Pro Pro Ile Ser Gln Gln Val 620 625 630 ctc cag ccc cct ccc tca ccacag gga ttt gtg caa cag cct ccg cct 2272 Leu Gln Pro Pro Pro Ser Pro GlnGly Phe Val Gln Gln Pro Pro Pro 635 640 645 gca cag atg cct gta tat tattac cca tct ggt cag tac cct acc tca 2320 Ala Gln Met Pro Val Tyr Tyr TyrPro Ser Gly Gln Tyr Pro Thr Ser 650 655 660 acc acg caa cag tac cgg cccatg gcc ccg gtt cag tac aac gct cag 2368 Thr Thr Gln Gln Tyr Arg Pro MetAla Pro Val Gln Tyr Asn Ala Gln 665 670 675 680 agg agt caa cag atg ccacag gca gca cag caa gca ggt tac cag cca 2416 Arg Ser Gln Gln Met Pro GlnAla Ala Gln Gln Ala Gly Tyr Gln Pro 685 690 695 gtc ttg tct ggt caa caggga ttc caa ggc cta ata gga gtg cag cag 2464 Val Leu Ser Gly Gln Gln GlyPhe Gln Gly Leu Ile Gly Val Gln Gln 700 705 710 cca cct cag agt cag aacgtg ata aat aac caa caa gga act ccg gtg 2512 Pro Pro Gln Ser Gln Asn ValIle Asn Asn Gln Gln Gly Thr Pro Val 715 720 725 caa agc gtg atg gtt tcctac cca aca atg tct tct tat cag gtg cca 2560 Gln Ser Val Met Val Ser TyrPro Thr Met Ser Ser Tyr Gln Val Pro 730 735 740 atg acc cag ggt tct caagga ctg ccc cag cag tca tac caa cag cca 2608 Met Thr Gln Gly Ser Gln GlyLeu Pro Gln Gln Ser Tyr Gln Gln Pro 745 750 755 760 atc atg cta cct aaccag gca ggt caa ggg tca ctc cca gcc act gga 2656 Ile Met Leu Pro Asn GlnAla Gly Gln Gly Ser Leu Pro Ala Thr Gly 765 770 775 atg cct gtt tac tgtaat gtc aca ccg ccc acc cct cag aac aac ctt 2704 Met Pro Val Tyr Cys AsnVal Thr Pro Pro Thr Pro Gln Asn Asn Leu 780 785 790 agg ctg att ggc ccacac tgc ccc tcc agc act gtc cca gtg atg tca 2752 Arg Leu Ile Gly Pro HisCys Pro Ser Ser Thr Val Pro Val Met Ser 795 800 805 gct agc tgc aga acaaac tgt gca agt atg agc aat gct ggt tgg cag 2800 Ala Ser Cys Arg Thr AsnCys Ala Ser Met Ser Asn Ala Gly Trp Gln 810 815 820 gtc aaa ttc tgagagctctggc tgtggtacat ttcttcagat atttctcatg 2852 Val Lys Phe 825gcctttgatg gaagaggaac aaggtgggaa aactggctga ggacttaagt attcactcaa 2912cactcaaatg attgctgctg gtattctgta aaaaataaac aaagactaat atacacgtta 2972gctggttaat ggtgcatatt tctgtcatgt ctgctaggta tgcctttata gcttagctag 3032tgacatgaat tcatcaaggt aagattttct cctaccactg aataccactg tgtagattat 3092aatatcccta atttggatta gttttgtact ttgtgttgag tttgtgatgc taaaagtatt 3152taaaaattat atactaaatc acattgtacc aaagctgtaa tggaaaagca aagaagaatt 3212gatgaattga aggaataatt tatatacatt atagagtttt cttttttaat ggatatatac 3272tgtattgtag tgtttaatca aaataaaact atttgacctt atggaggaag gtcatgtttt 3332taaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aa 3374 4 827 PRT Homosapiens 4 Met Ser Glu Gln Gly Asp Leu Asn Gln Ala Ile Ala Glu Glu GlyGly 1 5 10 15 Thr Glu Gln Glu Thr Ala Thr Pro Glu Asn Gly Ile Val LysSer Glu 20 25 30 Ser Leu Asp Glu Glu Glu Lys Leu Glu Leu Gln Arg Arg LeuGlu Ala 35 40 45 Gln Asn Gln Glu Arg Arg Lys Ser Lys Ser Gly Ala Gly LysGly Lys 50 55 60 Leu Thr Arg Ser Leu Ala Val Cys Glu Glu Ser Ser Ala ArgPro Gly 65 70 75 80 Gly Glu Ser Leu Gln Asp Gln Glu Ser Ile His Leu GlnLeu Ser Ser 85 90 95 Phe Ser Ser Leu Gln Glu Glu Asp Lys Ser Arg Lys AspAsp Ser Glu 100 105 110 Arg Glu Lys Glu Lys Asp Lys Asn Lys Asp Lys ThrSer Glu Lys Pro 115 120 125 Lys Ile Arg Met Leu Ser Lys Asp Cys Ser GlnGlu Tyr Thr Asp Ser 130 135 140 Thr Gly Ile Asp Leu His Glu Phe Leu IleAsn Thr Leu Lys Asn Asn 145 150 155 160 Ser Arg Asp Arg Met Ile Leu LeuLys Met Glu Gln Glu Ile Ile Asp 165 170 175 Phe Ile Ala Asp Asn Asn AsnHis Tyr Lys Lys Phe Pro Gln Met Ser 180 185 190 Ser Tyr Gln Arg Met LeuVal His Arg Val Ala Ala Tyr Phe Gly Leu 195 200 205 Asp His Asn Val AspGln Thr Gly Lys Ser Val Ile Ile Asn Lys Thr 210 215 220 Ser Ser Thr ArgIle Pro Glu Gln Arg Phe Cys Glu His Leu Lys Asp 225 230 235 240 Glu LysGly Glu Glu Ser Gln Lys Arg Phe Ile Leu Lys Arg Asp Asn 245 250 255 SerSer Ile Asp Lys Glu Asp Asn Gln Gln Asn Arg Met His Pro Phe 260 265 270Arg Asp Asp Arg Arg Ser Lys Ser Ile Glu Glu Arg Glu Glu Glu Tyr 275 280285 Gln Arg Val Arg Glu Arg Ile Phe Ala His Asp Ser Val Cys Ser Gln 290295 300 Glu Ser Leu Phe Val Glu Asn Arg Gly Asn Arg Asp Gly Ser Gly Arg305 310 315 320 Thr Ser Gly Ser Arg Gln Ser Ser Ser Glu Asn Glu Leu LysTrp Ser 325 330 335 Asp His Gln Arg Ala Trp Ser Ser Thr Asp Ser Asp SerSer Asn Arg 340 345 350 Asn Leu Lys Pro Ala Met Thr Lys Thr Ala Ser PheGly Gly Ile Thr 355 360 365 Val Leu Thr Arg Gly Asp Ser Thr Ser Ser ThrArg Ser Thr Gly Lys 370 375 380 Leu Ser Lys Ala Gly Ser Glu Ser Ser SerSer Ala Gly Ser Ser Gly 385 390 395 400 Ser Leu Ser Arg Thr His Pro ProLeu Gln Ser Thr Pro Leu Val Ser 405 410 415 Gly Val Ala Ala Gly Ser ProGly Cys Val Pro Tyr Pro Glu Asn Gly 420 425 430 Ile Gly Gly Gln Val AlaPro Ser Ser Thr Ser Tyr Ile Leu Leu Pro 435 440 445 Leu Glu Ala Ala ThrGly Ile Pro Pro Gly Ser Ile Leu Leu Asn Pro 450 455 460 His Thr Gly GlnPro Phe Val Asn Pro Asp Gly Thr Pro Ala Ile Tyr 465 470 475 480 Asn ProPro Thr Ser Gln Gln Pro Leu Arg Ser Ala Met Val Gly Gln 485 490 495 SerGln Gln Gln Pro Pro Gln Gln Gln Pro Ser Pro Gln Pro Gln Gln 500 505 510Gln Val Gln Pro Pro Gln Pro Gln Met Ala Gly Pro Leu Val Thr Gln 515 520525 Ser Val Gln Gly Leu Gln Ala Ser Ser Gln Ser Val Gln Tyr Pro Ala 530535 540 Val Ser Phe Pro Pro Gln His Leu Leu Pro Val Ser Pro Thr Gln His545 550 555 560 Phe Pro Met Arg Asp Asp Val Ala Thr Gln Phe Gly Gln MetThr Leu 565 570 575 Ser Arg Gln Ser Ser Gly Glu Thr Pro Glu Pro Pro SerGly Pro Val 580 585 590 Tyr Pro Ser Ser Leu Met Pro Gln Pro Ala Gln GlnPro Ser Tyr Val 595 600 605 Ile Ala Ser Thr Gly Gln Gln Leu Pro Thr GlyGly Phe Ser Gly Ser 610 615 620 Gly Pro Pro Ile Ser Gln Gln Val Leu GlnPro Pro Pro Ser Pro Gln 625 630 635 640 Gly Phe Val Gln Gln Pro Pro ProAla Gln Met Pro Val Tyr Tyr Tyr 645 650 655 Pro Ser Gly Gln Tyr Pro ThrSer Thr Thr Gln Gln Tyr Arg Pro Met 660 665 670 Ala Pro Val Gln Tyr AsnAla Gln Arg Ser Gln Gln Met Pro Gln Ala 675 680 685 Ala Gln Gln Ala GlyTyr Gln Pro Val Leu Ser Gly Gln Gln Gly Phe 690 695 700 Gln Gly Leu IleGly Val Gln Gln Pro Pro Gln Ser Gln Asn Val Ile 705 710 715 720 Asn AsnGln Gln Gly Thr Pro Val Gln Ser Val Met Val Ser Tyr Pro 725 730 735 ThrMet Ser Ser Tyr Gln Val Pro Met Thr Gln Gly Ser Gln Gly Leu 740 745 750Pro Gln Gln Ser Tyr Gln Gln Pro Ile Met Leu Pro Asn Gln Ala Gly 755 760765 Gln Gly Ser Leu Pro Ala Thr Gly Met Pro Val Tyr Cys Asn Val Thr 770775 780 Pro Pro Thr Pro Gln Asn Asn Leu Arg Leu Ile Gly Pro His Cys Pro785 790 795 800 Ser Ser Thr Val Pro Val Met Ser Ala Ser Cys Arg Thr AsnCys Ala 805 810 815 Ser Met Ser Asn Ala Gly Trp Gln Val Lys Phe 820 8255 3332 DNA Homo sapiens CDS (329)..(2770) 5 gtctattttt aatgctatttaatgaaggag cgagcgcctc actcagcaat aaaagaagca 60 tgagggaaga cagagcagtgcatggttatg gatactggac aaggatattt ggaaaggttg 120 acgatgtgtc acactgtgtaagggaatcgc atggagatgg gcattccgaa ctgttaatgg 180 ggacatggga ctccagttgtctctgatcac ttgtgtggat tttcctggcg tagaacgaca 240 gaagccgcta gtaagtcgccaagacctaca gcaggaattc tgcaccaaag ggcataaaat 300 cttgttattt taatttgcatctgggaga atg tct gag caa gga gac ctg aat 352 Met Ser Glu Gln Gly Asp LeuAsn 1 5 cag gca ata gca gag gaa gga ggg act gag cag gag acg gcc act cca400 Gln Ala Ile Ala Glu Glu Gly Gly Thr Glu Gln Glu Thr Ala Thr Pro 1015 20 gag aac ggc att gtt aaa tca gaa agt ctg gat gaa gag gag aaa ctg448 Glu Asn Gly Ile Val Lys Ser Glu Ser Leu Asp Glu Glu Glu Lys Leu 2530 35 40 gaa ctg cag agg cgg ctg gag gct cag aat caa gaa aga aga aaa tcc496 Glu Leu Gln Arg Arg Leu Glu Ala Gln Asn Gln Glu Arg Arg Lys Ser 4550 55 aag tca gga gca gga aaa ggt aaa ctg act cgc agt ctt gct gtc tgt544 Lys Ser Gly Ala Gly Lys Gly Lys Leu Thr Arg Ser Leu Ala Val Cys 6065 70 gag gaa tct tct gcc aga cca gga ggt gaa agt ctt cag gat cag gaa592 Glu Glu Ser Ser Ala Arg Pro Gly Gly Glu Ser Leu Gln Asp Gln Glu 7580 85 tca att cat tta cag ctt tcc agt ttt tcc agc ctg caa gag gag gat640 Ser Ile His Leu Gln Leu Ser Ser Phe Ser Ser Leu Gln Glu Glu Asp 9095 100 aaa tct agg aaa gat gac tct gaa aga gaa aaa gaa aag gat aaa aac688 Lys Ser Arg Lys Asp Asp Ser Glu Arg Glu Lys Glu Lys Asp Lys Asn 105110 115 120 aaa gat aaa acc tct gaa aaa ccc aag atc aga atg tta tca aaagat 736 Lys Asp Lys Thr Ser Glu Lys Pro Lys Ile Arg Met Leu Ser Lys Asp125 130 135 tgc agc caa gaa tac acg gat tct aca ggc ata gac tta cac gagttt 784 Cys Ser Gln Glu Tyr Thr Asp Ser Thr Gly Ile Asp Leu His Glu Phe140 145 150 ctg att aac aca tta aag aat aat tcc agg gac agg atg ata cttttg 832 Leu Ile Asn Thr Leu Lys Asn Asn Ser Arg Asp Arg Met Ile Leu Leu155 160 165 aaa atg gag cag gaa att att gat ttc att gct gac aac aat aatcat 880 Lys Met Glu Gln Glu Ile Ile Asp Phe Ile Ala Asp Asn Asn Asn His170 175 180 tat aaa aag ttc cct cag atg tca tcg tat cag agg atg ctt gtccat 928 Tyr Lys Lys Phe Pro Gln Met Ser Ser Tyr Gln Arg Met Leu Val His185 190 195 200 cga gtg gca gct tat ttt gga ttg gat cac aat gtg gat caaaca gga 976 Arg Val Ala Ala Tyr Phe Gly Leu Asp His Asn Val Asp Gln ThrGly 205 210 215 aaa tct gtt atc atc aac aag acc agc agc acc aga ata ccagag caa 1024 Lys Ser Val Ile Ile Asn Lys Thr Ser Ser Thr Arg Ile Pro GluGln 220 225 230 agg ttt tgt gaa cat tta aaa gat gaa aaa ggt gaa gaa tcccag aag 1072 Arg Phe Cys Glu His Leu Lys Asp Glu Lys Gly Glu Glu Ser GlnLys 235 240 245 cgg ttt atc ttg aag cga gat aac tct agt att gat aaa gaagac aat 1120 Arg Phe Ile Leu Lys Arg Asp Asn Ser Ser Ile Asp Lys Glu AspAsn 250 255 260 cag tca gtt tgc tcc cag gaa agc ctt ttt gtg gaa aac agtagg ctc 1168 Gln Ser Val Cys Ser Gln Glu Ser Leu Phe Val Glu Asn Ser ArgLeu 265 270 275 280 ttg gaa gac agt aac ata tgc aat gag acc tat aag aaaaga cag ctc 1216 Leu Glu Asp Ser Asn Ile Cys Asn Glu Thr Tyr Lys Lys ArgGln Leu 285 290 295 ttt cgg ggc aac aga gat ggc tca ggg aga aca tct gggagt cga cag 1264 Phe Arg Gly Asn Arg Asp Gly Ser Gly Arg Thr Ser Gly SerArg Gln 300 305 310 agc agc tca gaa aat gaa ctc aag tgg tct gac cac caaagg gcc tgg 1312 Ser Ser Ser Glu Asn Glu Leu Lys Trp Ser Asp His Gln ArgAla Trp 315 320 325 agc agc aca gac tcc gac agt tcc aac cgc aat cta aagccc gcc atg 1360 Ser Ser Thr Asp Ser Asp Ser Ser Asn Arg Asn Leu Lys ProAla Met 330 335 340 acc aag acg gcg agt ttt ggg ggc atc acg gtg ctg accagg ggt gac 1408 Thr Lys Thr Ala Ser Phe Gly Gly Ile Thr Val Leu Thr ArgGly Asp 345 350 355 360 agc act tcc agt act agg agt acc ggg aag ctg tccaaa gca ggt tcc 1456 Ser Thr Ser Ser Thr Arg Ser Thr Gly Lys Leu Ser LysAla Gly Ser 365 370 375 gag tct tcc agc agt gca ggc tcc tca gga tcg ctgtcc cgc acc cat 1504 Glu Ser Ser Ser Ser Ala Gly Ser Ser Gly Ser Leu SerArg Thr His 380 385 390 cca cct ctc cag agc aca ccc cta gtc tca ggt gtggca gct ggc tct 1552 Pro Pro Leu Gln Ser Thr Pro Leu Val Ser Gly Val AlaAla Gly Ser 395 400 405 cca ggc tgt gtg cct tat cca gag aat gga ata gggggc cag gtt gct 1600 Pro Gly Cys Val Pro Tyr Pro Glu Asn Gly Ile Gly GlyGln Val Ala 410 415 420 ccc agc agc acc agc tac atc ctc ctt cca ctt gaagct gca aca ggc 1648 Pro Ser Ser Thr Ser Tyr Ile Leu Leu Pro Leu Glu AlaAla Thr Gly 425 430 435 440 atc ccg cct gga agc atc ctt ctt aat cca cacaca ggc cag ccc ttt 1696 Ile Pro Pro Gly Ser Ile Leu Leu Asn Pro His ThrGly Gln Pro Phe 445 450 455 gtg aat ccc gat gga act cct gca ata tac aaccca ccc acc agt cag 1744 Val Asn Pro Asp Gly Thr Pro Ala Ile Tyr Asn ProPro Thr Ser Gln 460 465 470 cag ccc ctg cga agc gcc atg gtg ggg cag tcccaa cag cag ccg cca 1792 Gln Pro Leu Arg Ser Ala Met Val Gly Gln Ser GlnGln Gln Pro Pro 475 480 485 cag cag cag ccc tcc ccg cag ccc caa cag caggtc cag cca ccg cag 1840 Gln Gln Gln Pro Ser Pro Gln Pro Gln Gln Gln ValGln Pro Pro Gln 490 495 500 cca cag atg gca ggc cct ctg gtc act cag tctgtc cag ggg ctg cag 1888 Pro Gln Met Ala Gly Pro Leu Val Thr Gln Ser ValGln Gly Leu Gln 505 510 515 520 gct tcc tcc cag tca gtg caa tat ccg gcagtc tct ttt cct ccc cag 1936 Ala Ser Ser Gln Ser Val Gln Tyr Pro Ala ValSer Phe Pro Pro Gln 525 530 535 cac ctc cta cct gtg tct cca acg cag cacttt ccc atg aga gat gat 1984 His Leu Leu Pro Val Ser Pro Thr Gln His PhePro Met Arg Asp Asp 540 545 550 gtg gca aca cag ttt ggc cag atg acc ctgagc cgg cag tcc tcg ggg 2032 Val Ala Thr Gln Phe Gly Gln Met Thr Leu SerArg Gln Ser Ser Gly 555 560 565 gag act cct gaa ccc cca tca ggt cct gtctac cca tcc tcc ctt atg 2080 Glu Thr Pro Glu Pro Pro Ser Gly Pro Val TyrPro Ser Ser Leu Met 570 575 580 cca cag ccg gcc cag cag ccc agc tat gtaatc gcc tct aca ggc cag 2128 Pro Gln Pro Ala Gln Gln Pro Ser Tyr Val IleAla Ser Thr Gly Gln 585 590 595 600 cag ctt cct aca gga gga ttc tca ggctct ggc cct ccc atc tcc cag 2176 Gln Leu Pro Thr Gly Gly Phe Ser Gly SerGly Pro Pro Ile Ser Gln 605 610 615 cag gtc ctc cag ccc cct ccc tca ccacag gga tty gtg caa cag cct 2224 Gln Val Leu Gln Pro Pro Pro Ser Pro GlnGly Phe Val Gln Gln Pro 620 625 630 ccg cct gca cag atg cct gta tat tattac cca tct ggt cag tac cct 2272 Pro Pro Ala Gln Met Pro Val Tyr Tyr TyrPro Ser Gly Gln Tyr Pro 635 640 645 acc tca acc acg caa cag tac cgg cccatg gcc ccg gtt cag tac aac 2320 Thr Ser Thr Thr Gln Gln Tyr Arg Pro MetAla Pro Val Gln Tyr Asn 650 655 660 gct cag agg agt caa cag atg cca caggca gca cag caa gca ggt tac 2368 Ala Gln Arg Ser Gln Gln Met Pro Gln AlaAla Gln Gln Ala Gly Tyr 665 670 675 680 cag cca gtc ttg tct ggt caa caggga ttc caa ggc cta ata gga gtg 2416 Gln Pro Val Leu Ser Gly Gln Gln GlyPhe Gln Gly Leu Ile Gly Val 685 690 695 cag cag cca cct cag agt cag aacgtg ata aat aac caa caa gga act 2464 Gln Gln Pro Pro Gln Ser Gln Asn ValIle Asn Asn Gln Gln Gly Thr 700 705 710 ccg gtg caa agc gtg atg gtt tcctac cca aca atg tct tct tat cag 2512 Pro Val Gln Ser Val Met Val Ser TyrPro Thr Met Ser Ser Tyr Gln 715 720 725 gtg cca atg acc cag ggt tct caagga ctg ccc cag cag tca tac caa 2560 Val Pro Met Thr Gln Gly Ser Gln GlyLeu Pro Gln Gln Ser Tyr Gln 730 735 740 cag cca atc atg cta cct aac caggca ggt caa ggg tca ctc cca gcc 2608 Gln Pro Ile Met Leu Pro Asn Gln AlaGly Gln Gly Ser Leu Pro Ala 745 750 755 760 act gga atg cct gtt tac tgtaat gtc aca ccg ccc acc cct cag aac 2656 Thr Gly Met Pro Val Tyr Cys AsnVal Thr Pro Pro Thr Pro Gln Asn 765 770 775 aac ctt agg ctg att ggc ccacac tgc ccc tcc agc act gtc cca gtg 2704 Asn Leu Arg Leu Ile Gly Pro HisCys Pro Ser Ser Thr Val Pro Val 780 785 790 atg tca gct agc tgc aga acaaac tgt gca agt atg agc aat gct ggt 2752 Met Ser Ala Ser Cys Arg Thr AsnCys Ala Ser Met Ser Asn Ala Gly 795 800 805 tgg cag gtc aaa ttc tgagagctctggc tgtggtacat ttcttcagat 2800 Trp Gln Val Lys Phe 810 atttctcatggcctttgatg gaagaggaac aaggtgggaa aactggctga ggacttaagt 2860 attcactcaacactcaaatg attgctgctg gtattctgta aaaartaaac aaagactaat 2920 atacacgttagctggttaat ggtgcatatt tctgtcatgt ctgctaggta tgcctttata 2980 gcttagctagtgacatgaat tcatcaaggt aagattytct cctaccactg aataccactg 3040 tgtagattataatatcccta atttggatta gttttgtact ttgtgttgag tttgtgatgc 3100 taaaagtatttaaaaattat atactaaatc acattgtacc aaagctgtaa tggaaaagca 3160 aagaagaaytgatgaattga aggaataatt tatatacatt atagagtttt cttttttaat 3220 ggatatatactgtattgtag tgtttaatca aaataaaact atttgacctt atggaggaag 3280 gtcatgtttttaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aa 3332 6 813 PRT Homosapiens 6 Met Ser Glu Gln Gly Asp Leu Asn Gln Ala Ile Ala Glu Glu GlyGly 1 5 10 15 Thr Glu Gln Glu Thr Ala Thr Pro Glu Asn Gly Ile Val LysSer Glu 20 25 30 Ser Leu Asp Glu Glu Glu Lys Leu Glu Leu Gln Arg Arg LeuGlu Ala 35 40 45 Gln Asn Gln Glu Arg Arg Lys Ser Lys Ser Gly Ala Gly LysGly Lys 50 55 60 Leu Thr Arg Ser Leu Ala Val Cys Glu Glu Ser Ser Ala ArgPro Gly 65 70 75 80 Gly Glu Ser Leu Gln Asp Gln Glu Ser Ile His Leu GlnLeu Ser Ser 85 90 95 Phe Ser Ser Leu Gln Glu Glu Asp Lys Ser Arg Lys AspAsp Ser Glu 100 105 110 Arg Glu Lys Glu Lys Asp Lys Asn Lys Asp Lys ThrSer Glu Lys Pro 115 120 125 Lys Ile Arg Met Leu Ser Lys Asp Cys Ser GlnGlu Tyr Thr Asp Ser 130 135 140 Thr Gly Ile Asp Leu His Glu Phe Leu IleAsn Thr Leu Lys Asn Asn 145 150 155 160 Ser Arg Asp Arg Met Ile Leu LeuLys Met Glu Gln Glu Ile Ile Asp 165 170 175 Phe Ile Ala Asp Asn Asn AsnHis Tyr Lys Lys Phe Pro Gln Met Ser 180 185 190 Ser Tyr Gln Arg Met LeuVal His Arg Val Ala Ala Tyr Phe Gly Leu 195 200 205 Asp His Asn Val AspGln Thr Gly Lys Ser Val Ile Ile Asn Lys Thr 210 215 220 Ser Ser Thr ArgIle Pro Glu Gln Arg Phe Cys Glu His Leu Lys Asp 225 230 235 240 Glu LysGly Glu Glu Ser Gln Lys Arg Phe Ile Leu Lys Arg Asp Asn 245 250 255 SerSer Ile Asp Lys Glu Asp Asn Gln Ser Val Cys Ser Gln Glu Ser 260 265 270Leu Phe Val Glu Asn Ser Arg Leu Leu Glu Asp Ser Asn Ile Cys Asn 275 280285 Glu Thr Tyr Lys Lys Arg Gln Leu Phe Arg Gly Asn Arg Asp Gly Ser 290295 300 Gly Arg Thr Ser Gly Ser Arg Gln Ser Ser Ser Glu Asn Glu Leu Lys305 310 315 320 Trp Ser Asp His Gln Arg Ala Trp Ser Ser Thr Asp Ser AspSer Ser 325 330 335 Asn Arg Asn Leu Lys Pro Ala Met Thr Lys Thr Ala SerPhe Gly Gly 340 345 350 Ile Thr Val Leu Thr Arg Gly Asp Ser Thr Ser SerThr Arg Ser Thr 355 360 365 Gly Lys Leu Ser Lys Ala Gly Ser Glu Ser SerSer Ser Ala Gly Ser 370 375 380 Ser Gly Ser Leu Ser Arg Thr His Pro ProLeu Gln Ser Thr Pro Leu 385 390 395 400 Val Ser Gly Val Ala Ala Gly SerPro Gly Cys Val Pro Tyr Pro Glu 405 410 415 Asn Gly Ile Gly Gly Gln ValAla Pro Ser Ser Thr Ser Tyr Ile Leu 420 425 430 Leu Pro Leu Glu Ala AlaThr Gly Ile Pro Pro Gly Ser Ile Leu Leu 435 440 445 Asn Pro His Thr GlyGln Pro Phe Val Asn Pro Asp Gly Thr Pro Ala 450 455 460 Ile Tyr Asn ProPro Thr Ser Gln Gln Pro Leu Arg Ser Ala Met Val 465 470 475 480 Gly GlnSer Gln Gln Gln Pro Pro Gln Gln Gln Pro Ser Pro Gln Pro 485 490 495 GlnGln Gln Val Gln Pro Pro Gln Pro Gln Met Ala Gly Pro Leu Val 500 505 510Thr Gln Ser Val Gln Gly Leu Gln Ala Ser Ser Gln Ser Val Gln Tyr 515 520525 Pro Ala Val Ser Phe Pro Pro Gln His Leu Leu Pro Val Ser Pro Thr 530535 540 Gln His Phe Pro Met Arg Asp Asp Val Ala Thr Gln Phe Gly Gln Met545 550 555 560 Thr Leu Ser Arg Gln Ser Ser Gly Glu Thr Pro Glu Pro ProSer Gly 565 570 575 Pro Val Tyr Pro Ser Ser Leu Met Pro Gln Pro Ala GlnGln Pro Ser 580 585 590 Tyr Val Ile Ala Ser Thr Gly Gln Gln Leu Pro ThrGly Gly Phe Ser 595 600 605 Gly Ser Gly Pro Pro Ile Ser Gln Gln Val LeuGln Pro Pro Pro Ser 610 615 620 Pro Gln Gly Phe Val Gln Gln Pro Pro ProAla Gln Met Pro Val Tyr 625 630 635 640 Tyr Tyr Pro Ser Gly Gln Tyr ProThr Ser Thr Thr Gln Gln Tyr Arg 645 650 655 Pro Met Ala Pro Val Gln TyrAsn Ala Gln Arg Ser Gln Gln Met Pro 660 665 670 Gln Ala Ala Gln Gln AlaGly Tyr Gln Pro Val Leu Ser Gly Gln Gln 675 680 685 Gly Phe Gln Gly LeuIle Gly Val Gln Gln Pro Pro Gln Ser Gln Asn 690 695 700 Val Ile Asn AsnGln Gln Gly Thr Pro Val Gln Ser Val Met Val Ser 705 710 715 720 Tyr ProThr Met Ser Ser Tyr Gln Val Pro Met Thr Gln Gly Ser Gln 725 730 735 GlyLeu Pro Gln Gln Ser Tyr Gln Gln Pro Ile Met Leu Pro Asn Gln 740 745 750Ala Gly Gln Gly Ser Leu Pro Ala Thr Gly Met Pro Val Tyr Cys Asn 755 760765 Val Thr Pro Pro Thr Pro Gln Asn Asn Leu Arg Leu Ile Gly Pro His 770775 780 Cys Pro Ser Ser Thr Val Pro Val Met Ser Ala Ser Cys Arg Thr Asn785 790 795 800 Cys Ala Ser Met Ser Asn Ala Gly Trp Gln Val Lys Phe 805810 7 3272 DNA Homo sapiens CDS (329)..(2710) 7 gtctattttt aatgctatttaatgaaggag cgagcgcctc actcagcaat aaaagaagca 60 tgagggaaga cagagcagtgcatggttatg gatactggac aaggatattt ggaaaggttg 120 acgatgtgtc acactgtgtaagggaatcgc atggagatgg gcattccgaa ctgttaatgg 180 ggacatggga ctccagttgtctctgatcac ttgtgtggat tttcctggcg tagaacgaca 240 gaagccgcta gtaagtcgccaagacctaca gcaggaattc tgcaccaaag ggcataaaat 300 cttgttattt taatttgcatctgggaga atg tct gag caa gga gac ctg aat 352 Met Ser Glu Gln Gly Asp LeuAsn 1 5 cag gca ata gca gag gaa gga ggg act gag cag gag acg gcc act cca400 Gln Ala Ile Ala Glu Glu Gly Gly Thr Glu Gln Glu Thr Ala Thr Pro 1015 20 gag aac ggc att gtt aaa tca gaa agt ctg gat gaa gag gag aaa ctg448 Glu Asn Gly Ile Val Lys Ser Glu Ser Leu Asp Glu Glu Glu Lys Leu 2530 35 40 gaa ctg cag agg cgg ctg gag gct cag aat caa gaa aga aga aaa tcc496 Glu Leu Gln Arg Arg Leu Glu Ala Gln Asn Gln Glu Arg Arg Lys Ser 4550 55 aag tca gga gca gga aaa ggt aaa ctg act cgc agt ctt gct gtc tgt544 Lys Ser Gly Ala Gly Lys Gly Lys Leu Thr Arg Ser Leu Ala Val Cys 6065 70 gag gaa tct tct gcc aga cca gga ggt gaa agt ctt cag gat cag gaa592 Glu Glu Ser Ser Ala Arg Pro Gly Gly Glu Ser Leu Gln Asp Gln Glu 7580 85 tca att cat tta cag ctt tcc agt ttt tcc agc ctg caa gag gag gat640 Ser Ile His Leu Gln Leu Ser Ser Phe Ser Ser Leu Gln Glu Glu Asp 9095 100 aaa tct agg aaa gat gac tct gaa aga gaa aaa gaa aag gat aaa aac688 Lys Ser Arg Lys Asp Asp Ser Glu Arg Glu Lys Glu Lys Asp Lys Asn 105110 115 120 aaa gat aaa acc tct gaa aaa ccc aag atc aga atg tta tca aaagat 736 Lys Asp Lys Thr Ser Glu Lys Pro Lys Ile Arg Met Leu Ser Lys Asp125 130 135 tgc agc caa gaa tac acg gat tct aca ggc ata gac tta cac gagttt 784 Cys Ser Gln Glu Tyr Thr Asp Ser Thr Gly Ile Asp Leu His Glu Phe140 145 150 ctg att aac aca tta aag aat aat tcc agg gac agg atg ata cttttg 832 Leu Ile Asn Thr Leu Lys Asn Asn Ser Arg Asp Arg Met Ile Leu Leu155 160 165 aaa atg gag cag gaa att att gat ttc att gct gac aac aat aatcat 880 Lys Met Glu Gln Glu Ile Ile Asp Phe Ile Ala Asp Asn Asn Asn His170 175 180 tat aaa aag ttc cct cag atg tca tcg tat cag agg atg ctt gtccat 928 Tyr Lys Lys Phe Pro Gln Met Ser Ser Tyr Gln Arg Met Leu Val His185 190 195 200 cga gtg gca gct tat ttt gga ttg gat cac aat gtg gat caaaca gga 976 Arg Val Ala Ala Tyr Phe Gly Leu Asp His Asn Val Asp Gln ThrGly 205 210 215 aaa tct gtt atc atc aac aag acc agc agc acc aga ata ccagag caa 1024 Lys Ser Val Ile Ile Asn Lys Thr Ser Ser Thr Arg Ile Pro GluGln 220 225 230 agg ttt tgt gaa cat tta aaa gat gaa aaa ggt gaa gaa tcccag aag 1072 Arg Phe Cys Glu His Leu Lys Asp Glu Lys Gly Glu Glu Ser GlnLys 235 240 245 cgg ttt atc ttg aag cga gat aac tct agt att gat aaa gaagac aat 1120 Arg Phe Ile Leu Lys Arg Asp Asn Ser Ser Ile Asp Lys Glu AspAsn 250 255 260 cag tca gtt tgc tcc cag gaa agc ctt ttt gtg gaa aac aggggc aac 1168 Gln Ser Val Cys Ser Gln Glu Ser Leu Phe Val Glu Asn Arg GlyAsn 265 270 275 280 aga gat ggc tca ggg aga aca tct ggg agt cga cag agcagc tca gaa 1216 Arg Asp Gly Ser Gly Arg Thr Ser Gly Ser Arg Gln Ser SerSer Glu 285 290 295 aat gaa ctc aag tgg tct gac cac caa agg gcc tgg agcagc aca gac 1264 Asn Glu Leu Lys Trp Ser Asp His Gln Arg Ala Trp Ser SerThr Asp 300 305 310 tcc gac agt tcc aac cgc aat cta aag ccc gcc atg accaag acg gcg 1312 Ser Asp Ser Ser Asn Arg Asn Leu Lys Pro Ala Met Thr LysThr Ala 315 320 325 agt ttt ggg ggc atc acg gtg ctg acc agg ggt gac agcact tcc agt 1360 Ser Phe Gly Gly Ile Thr Val Leu Thr Arg Gly Asp Ser ThrSer Ser 330 335 340 act agg agt acc ggg aag ctg tcc aaa gca ggt tcc gagtct tcc agc 1408 Thr Arg Ser Thr Gly Lys Leu Ser Lys Ala Gly Ser Glu SerSer Ser 345 350 355 360 agt gca ggc tcc tca gga tcg ctg tcc cgc acc catcca cct ctc cag 1456 Ser Ala Gly Ser Ser Gly Ser Leu Ser Arg Thr His ProPro Leu Gln 365 370 375 agc aca ccc cta gtc tca ggt gtg gca gct ggc tctcca ggc tgt gtg 1504 Ser Thr Pro Leu Val Ser Gly Val Ala Ala Gly Ser ProGly Cys Val 380 385 390 cct tat cca gag aat gga ata ggg ggc cag gtt gctccc agc agc acc 1552 Pro Tyr Pro Glu Asn Gly Ile Gly Gly Gln Val Ala ProSer Ser Thr 395 400 405 agc tac atc ctc ctt cca ctt gaa gct gca aca ggcatc ccg cct gga 1600 Ser Tyr Ile Leu Leu Pro Leu Glu Ala Ala Thr Gly IlePro Pro Gly 410 415 420 agc atc ctt ctt aat cca cac aca ggc cag ccc tttgtg aat ccc gat 1648 Ser Ile Leu Leu Asn Pro His Thr Gly Gln Pro Phe ValAsn Pro Asp 425 430 435 440 gga act cct gca ata tac aac cca ccc acc agtcag cag ccc ctg cga 1696 Gly Thr Pro Ala Ile Tyr Asn Pro Pro Thr Ser GlnGln Pro Leu Arg 445 450 455 agc gcc atg gtg ggg cag tcc caa cag cag ccgcca cag cag cag ccc 1744 Ser Ala Met Val Gly Gln Ser Gln Gln Gln Pro ProGln Gln Gln Pro 460 465 470 tcc ccg cag ccc caa cag cag gtc cag cca ccgcag cca cag atg gca 1792 Ser Pro Gln Pro Gln Gln Gln Val Gln Pro Pro GlnPro Gln Met Ala 475 480 485 ggc cct ctg gtc act cag tct gtc cag ggg ctgcag gct tcc tcc cag 1840 Gly Pro Leu Val Thr Gln Ser Val Gln Gly Leu GlnAla Ser Ser Gln 490 495 500 tca gtg caa tat ccg gca gtc tct ttt cct ccccag cac ctc cta cct 1888 Ser Val Gln Tyr Pro Ala Val Ser Phe Pro Pro GlnHis Leu Leu Pro 505 510 515 520 gtg tct cca acg cag cac ttt ccc atg agagat gat gtg gca aca cag 1936 Val Ser Pro Thr Gln His Phe Pro Met Arg AspAsp Val Ala Thr Gln 525 530 535 ttt ggc cag atg acc ctg agc cgg cag tcctcg ggg gag act cct gaa 1984 Phe Gly Gln Met Thr Leu Ser Arg Gln Ser SerGly Glu Thr Pro Glu 540 545 550 ccc cca tca ggt cct gtc tac cca tcc tccctt atg cca cag ccg gcc 2032 Pro Pro Ser Gly Pro Val Tyr Pro Ser Ser LeuMet Pro Gln Pro Ala 555 560 565 cag cag ccc agc tat gta atc gcc tct acaggc cag cag ctt cct aca 2080 Gln Gln Pro Ser Tyr Val Ile Ala Ser Thr GlyGln Gln Leu Pro Thr 570 575 580 gga gga ttc tca ggc tct ggc cct ccc atctcc cag cag gtc ctc cag 2128 Gly Gly Phe Ser Gly Ser Gly Pro Pro Ile SerGln Gln Val Leu Gln 585 590 595 600 ccc cct ccc tca cca cag gga tty gtgcaa cag cct ccg cct gca cag 2176 Pro Pro Pro Ser Pro Gln Gly Phe Val GlnGln Pro Pro Pro Ala Gln 605 610 615 atg cct gta tat tat tac cca tct ggtcag tac cct acc tca acc acg 2224 Met Pro Val Tyr Tyr Tyr Pro Ser Gly GlnTyr Pro Thr Ser Thr Thr 620 625 630 caa cag tac cgg ccc atg gcc ccg gttcag tac aac gct cag agg agt 2272 Gln Gln Tyr Arg Pro Met Ala Pro Val GlnTyr Asn Ala Gln Arg Ser 635 640 645 caa cag atg cca cag gca gca cag caagca ggt tac cag cca gtc ttg 2320 Gln Gln Met Pro Gln Ala Ala Gln Gln AlaGly Tyr Gln Pro Val Leu 650 655 660 tct ggt caa cag gga ttc caa ggc ctaata gga gtg cag cag cca cct 2368 Ser Gly Gln Gln Gly Phe Gln Gly Leu IleGly Val Gln Gln Pro Pro 665 670 675 680 cag agt cag aac gtg ata aat aaccaa caa gga act ccg gtg caa agc 2416 Gln Ser Gln Asn Val Ile Asn Asn GlnGln Gly Thr Pro Val Gln Ser 685 690 695 gtg atg gtt tcc tac cca aca atgtct tct tat cag gtg cca atg acc 2464 Val Met Val Ser Tyr Pro Thr Met SerSer Tyr Gln Val Pro Met Thr 700 705 710 cag ggt tct caa gga ctg ccc cagcag tca tac caa cag cca atc atg 2512 Gln Gly Ser Gln Gly Leu Pro Gln GlnSer Tyr Gln Gln Pro Ile Met 715 720 725 cta cct aac cag gca ggt caa gggtca ctc cca gcc act gga atg cct 2560 Leu Pro Asn Gln Ala Gly Gln Gly SerLeu Pro Ala Thr Gly Met Pro 730 735 740 gtt tac tgt aat gtc aca ccg cccacc cct cag aac aac ctt agg ctg 2608 Val Tyr Cys Asn Val Thr Pro Pro ThrPro Gln Asn Asn Leu Arg Leu 745 750 755 760 att ggc cca cac tgc ccc tccagc act gtc cca gtg atg tca gct agc 2656 Ile Gly Pro His Cys Pro Ser SerThr Val Pro Val Met Ser Ala Ser 765 770 775 tgc aga aca aac tgt gca agtatg agc aat gct ggt tgg cag gtc aaa 2704 Cys Arg Thr Asn Cys Ala Ser MetSer Asn Ala Gly Trp Gln Val Lys 780 785 790 ttc tga gagctctggctgtggtacat ttcttcagat atttctcatg gcctttgatg 2760 Phe gaagaggaacaaggtgggaa aactggctga ggacttaagt attcactcaa cactcaaatg 2820 attgctgctggtattctgta aaaartaaac aaagactaat atacacgtta gctggttaat 2880 ggtgcatatttctgtcatgt ctgctaggta tgcctttata gcttagctag tgacatgaat 2940 tcatcaaggtaagattytct cctaccactg aataccactg tgtagattat aatatcccta 3000 atttggattagttttgtact ttgtgttgag tttgtgatgc taaaagtatt taaaaattat 3060 atactaaatcacattgtacc aaagctgtaa tggaaaagca aagaagaayt gatgaattga 3120 aggaataatttatatacatt atagagtttt cttttttaat ggatatatac tgtattgtag 3180 tgtttaatcaaaataaaact atttgacctt atggaggaag gtcatgtttt taaaaaaaaa 3240 aaaaaaaaaaaaaaaaaaaa aaaaaaaaaa aa 3272 8 793 PRT Homo sapiens 8 Met Ser Glu GlnGly Asp Leu Asn Gln Ala Ile Ala Glu Glu Gly Gly 1 5 10 15 Thr Glu GlnGlu Thr Ala Thr Pro Glu Asn Gly Ile Val Lys Ser Glu 20 25 30 Ser Leu AspGlu Glu Glu Lys Leu Glu Leu Gln Arg Arg Leu Glu Ala 35 40 45 Gln Asn GlnGlu Arg Arg Lys Ser Lys Ser Gly Ala Gly Lys Gly Lys 50 55 60 Leu Thr ArgSer Leu Ala Val Cys Glu Glu Ser Ser Ala Arg Pro Gly 65 70 75 80 Gly GluSer Leu Gln Asp Gln Glu Ser Ile His Leu Gln Leu Ser Ser 85 90 95 Phe SerSer Leu Gln Glu Glu Asp Lys Ser Arg Lys Asp Asp Ser Glu 100 105 110 ArgGlu Lys Glu Lys Asp Lys Asn Lys Asp Lys Thr Ser Glu Lys Pro 115 120 125Lys Ile Arg Met Leu Ser Lys Asp Cys Ser Gln Glu Tyr Thr Asp Ser 130 135140 Thr Gly Ile Asp Leu His Glu Phe Leu Ile Asn Thr Leu Lys Asn Asn 145150 155 160 Ser Arg Asp Arg Met Ile Leu Leu Lys Met Glu Gln Glu Ile IleAsp 165 170 175 Phe Ile Ala Asp Asn Asn Asn His Tyr Lys Lys Phe Pro GlnMet Ser 180 185 190 Ser Tyr Gln Arg Met Leu Val His Arg Val Ala Ala TyrPhe Gly Leu 195 200 205 Asp His Asn Val Asp Gln Thr Gly Lys Ser Val IleIle Asn Lys Thr 210 215 220 Ser Ser Thr Arg Ile Pro Glu Gln Arg Phe CysGlu His Leu Lys Asp 225 230 235 240 Glu Lys Gly Glu Glu Ser Gln Lys ArgPhe Ile Leu Lys Arg Asp Asn 245 250 255 Ser Ser Ile Asp Lys Glu Asp AsnGln Ser Val Cys Ser Gln Glu Ser 260 265 270 Leu Phe Val Glu Asn Arg GlyAsn Arg Asp Gly Ser Gly Arg Thr Ser 275 280 285 Gly Ser Arg Gln Ser SerSer Glu Asn Glu Leu Lys Trp Ser Asp His 290 295 300 Gln Arg Ala Trp SerSer Thr Asp Ser Asp Ser Ser Asn Arg Asn Leu 305 310 315 320 Lys Pro AlaMet Thr Lys Thr Ala Ser Phe Gly Gly Ile Thr Val Leu 325 330 335 Thr ArgGly Asp Ser Thr Ser Ser Thr Arg Ser Thr Gly Lys Leu Ser 340 345 350 LysAla Gly Ser Glu Ser Ser Ser Ser Ala Gly Ser Ser Gly Ser Leu 355 360 365Ser Arg Thr His Pro Pro Leu Gln Ser Thr Pro Leu Val Ser Gly Val 370 375380 Ala Ala Gly Ser Pro Gly Cys Val Pro Tyr Pro Glu Asn Gly Ile Gly 385390 395 400 Gly Gln Val Ala Pro Ser Ser Thr Ser Tyr Ile Leu Leu Pro LeuGlu 405 410 415 Ala Ala Thr Gly Ile Pro Pro Gly Ser Ile Leu Leu Asn ProHis Thr 420 425 430 Gly Gln Pro Phe Val Asn Pro Asp Gly Thr Pro Ala IleTyr Asn Pro 435 440 445 Pro Thr Ser Gln Gln Pro Leu Arg Ser Ala Met ValGly Gln Ser Gln 450 455 460 Gln Gln Pro Pro Gln Gln Gln Pro Ser Pro GlnPro Gln Gln Gln Val 465 470 475 480 Gln Pro Pro Gln Pro Gln Met Ala GlyPro Leu Val Thr Gln Ser Val 485 490 495 Gln Gly Leu Gln Ala Ser Ser GlnSer Val Gln Tyr Pro Ala Val Ser 500 505 510 Phe Pro Pro Gln His Leu LeuPro Val Ser Pro Thr Gln His Phe Pro 515 520 525 Met Arg Asp Asp Val AlaThr Gln Phe Gly Gln Met Thr Leu Ser Arg 530 535 540 Gln Ser Ser Gly GluThr Pro Glu Pro Pro Ser Gly Pro Val Tyr Pro 545 550 555 560 Ser Ser LeuMet Pro Gln Pro Ala Gln Gln Pro Ser Tyr Val Ile Ala 565 570 575 Ser ThrGly Gln Gln Leu Pro Thr Gly Gly Phe Ser Gly Ser Gly Pro 580 585 590 ProIle Ser Gln Gln Val Leu Gln Pro Pro Pro Ser Pro Gln Gly Phe 595 600 605Val Gln Gln Pro Pro Pro Ala Gln Met Pro Val Tyr Tyr Tyr Pro Ser 610 615620 Gly Gln Tyr Pro Thr Ser Thr Thr Gln Gln Tyr Arg Pro Met Ala Pro 625630 635 640 Val Gln Tyr Asn Ala Gln Arg Ser Gln Gln Met Pro Gln Ala AlaGln 645 650 655 Gln Ala Gly Tyr Gln Pro Val Leu Ser Gly Gln Gln Gly PheGln Gly 660 665 670 Leu Ile Gly Val Gln Gln Pro Pro Gln Ser Gln Asn ValIle Asn Asn 675 680 685 Gln Gln Gly Thr Pro Val Gln Ser Val Met Val SerTyr Pro Thr Met 690 695 700 Ser Ser Tyr Gln Val Pro Met Thr Gln Gly SerGln Gly Leu Pro Gln 705 710 715 720 Gln Ser Tyr Gln Gln Pro Ile Met LeuPro Asn Gln Ala Gly Gln Gly 725 730 735 Ser Leu Pro Ala Thr Gly Met ProVal Tyr Cys Asn Val Thr Pro Pro 740 745 750 Thr Pro Gln Asn Asn Leu ArgLeu Ile Gly Pro His Cys Pro Ser Ser 755 760 765 Thr Val Pro Val Met SerAla Ser Cys Arg Thr Asn Cys Ala Ser Met 770 775 780 Ser Asn Ala Gly TrpGln Val Lys Phe 785 790 9 1006 DNA Homo sapiens CDS (280)..(549) 9gggcagcttg agacaggtgg agctggatca agctgtgaac gtgatttgct ggaagctggt 60cattagtgtt gacgatgtgt cacactgtgt aagggaatcg catggagatg ggcattccga 120actgttaatg gggacatggg actccagttg tctctgatca cttgtgtgga ttttcctggc 180gtagaacgac agaagccgct agtaagtcgc caagacctac agcaggaatt ctgcaccaaa 240gggcataaaa tcttgttatt ttaatttgca tctgggaga atg tct gag caa gga 294 MetSer Glu Gln Gly 1 5 gac ctg aat cag gca ata gca gag gaa gga ggg act gagcag gag acg 342 Asp Leu Asn Gln Ala Ile Ala Glu Glu Gly Gly Thr Glu GlnGlu Thr 10 15 20 gcc act cca gag aac ggc att gtt aaa tca gaa agt ctg gatgaa gag 390 Ala Thr Pro Glu Asn Gly Ile Val Lys Ser Glu Ser Leu Asp GluGlu 25 30 35 gag aaa ctg gaa ctg cag agg cgg ctg gag gct cag aat caa gaaaga 438 Glu Lys Leu Glu Leu Gln Arg Arg Leu Glu Ala Gln Asn Gln Glu Arg40 45 50 aga aaa tcc aag tca gga gca gga aaa ggt aaa ctg act cgc agt ctt486 Arg Lys Ser Lys Ser Gly Ala Gly Lys Gly Lys Leu Thr Arg Ser Leu 5560 65 gct gtc tgt gag gaa tct tct gcc aga cca gga ggt gaa agt ctt cag534 Ala Val Cys Glu Glu Ser Ser Ala Arg Pro Gly Gly Glu Ser Leu Gln 7075 80 85 gat cag act ctc tga aaactgcaaa tggaaaggaa ttcaaaagaa tttagattaa589 Asp Gln Thr Leu aagttaaata aaaagtaggc acagtagtgc tgaattttcctcaaaggctc tcttttgata 649 aggctgaacc aaatataatc ccaagtatcc tctctccttccttgttggag atgtcttacc 709 tctcagctcc caaaatgcac ttgcctataa gaaacacaattgctggttca tatgaaactt 769 wagaaatagt gaataaggtg catttaactt tggagaaatacttttatgsc tttggtggag 829 atttctcaat actgcaaaag ttgtccagaa atgaatctgagctgatggtg actttaagtt 889 aatattatta atatatcact gcatattttt acccttatttttgctcctta cagcaagatt 949 agtaggttat aaaaatttaa atttaaacaa aattatttcatgacaaaatg ggaaact 1006 10 89 PRT Homo sapiens 10 Met Ser Glu Gln GlyAsp Leu Asn Gln Ala Ile Ala Glu Glu Gly Gly 1 5 10 15 Thr Glu Gln GluThr Ala Thr Pro Glu Asn Gly Ile Val Lys Ser Glu 20 25 30 Ser Leu Asp GluGlu Glu Lys Leu Glu Leu Gln Arg Arg Leu Glu Ala 35 40 45 Gln Asn Gln GluArg Arg Lys Ser Lys Ser Gly Ala Gly Lys Gly Lys 50 55 60 Leu Thr Arg SerLeu Ala Val Cys Glu Glu Ser Ser Ala Arg Pro Gly 65 70 75 80 Gly Glu SerLeu Gln Asp Gln Thr Leu 85 11 807 PRT Mus musculus 11 Met Ser Glu GlnGly Gly Leu Thr Pro Thr Ile Leu Glu Glu Gly Gln 1 5 10 15 Thr Glu ProGlu Ser Ala Pro Glu Asn Gly Ile Leu Lys Ser Glu Ser 20 25 30 Leu Asp GluGlu Glu Lys Leu Glu Leu Gln Arg Arg Leu Ala Ala Gln 35 40 45 Asn Gln GluArg Arg Lys Ser Lys Ser Gly Ala Gly Lys Gly Lys Leu 50 55 60 Thr Arg SerLeu Ala Val Cys Glu Glu Ser Ser Ala Arg Ser Gly Gly 65 70 75 80 Glu SerHis Gln Asp Gln Glu Ser Ile His Leu Gln Leu Ser Ser Phe 85 90 95 Pro SerLeu Gln Glu Glu Asp Lys Ser Arg Lys Asp Asp Ser Glu Arg 100 105 110 GluLys Glu Lys Asp Lys Asn Arg Glu Lys Leu Ser Glu Arg Pro Lys 115 120 125Ile Arg Met Leu Ser Lys Asp Cys Ser Gln Glu Tyr Thr Asp Ser Thr 130 135140 Gly Ile Asp Leu His Gly Phe Leu Ile Asn Thr Leu Lys Asn Asn Ser 145150 155 160 Arg Asp Arg Met Ile Leu Leu Lys Met Glu Gln Glu Met Ile AspPhe 165 170 175 Ile Ala Asp Ser Asn Asn His Tyr Lys Lys Phe Pro Gln MetSer Ser 180 185 190 Tyr Gln Arg Met Leu Val His Arg Val Ala Ala Tyr PheGly Leu Asp 195 200 205 His Asn Val Asp Gln Thr Gly Lys Ser Val Ile IleAsn Lys Thr Ser 210 215 220 Ser Thr Arg Ile Pro Glu Gln Arg Phe Cys GluHis Leu Lys Asp Glu 225 230 235 240 Lys Ser Glu Glu Ser Gln Lys Arg PheIle Leu Lys Arg Asp Asn Ser 245 250 255 Ser Ile Asp Lys Glu Asp Asn GlnAsn Arg Met His Pro Phe Arg Asp 260 265 270 Asp Arg Arg Ser Lys Ser IleGlu Glu Arg Glu Glu Glu Tyr Gln Arg 275 280 285 Val Arg Glu Arg Ile PheAla His Asp Ser Val Cys Ser Gln Glu Ser 290 295 300 Leu Phe Leu Asp AsnSer Arg Leu Gln Glu Asp Met His Ile Cys Asn 305 310 315 320 Glu Thr TyrLys Lys Arg Gln Leu Phe Arg Ala His Arg Asp Ser Ser 325 330 335 Gly ArgThr Ser Gly Ser Arg Gln Ser Ser Ser Glu Thr Glu Leu Arg 340 345 350 TrpPro Asp His Gln Arg Ala Trp Ser Ser Thr Asp Ser Asp Ser Ser 355 360 365Asn Arg Asn Leu Lys Pro Thr Met Thr Lys Thr Ala Ser Phe Gly Gly 370 375380 Ile Thr Val Leu Thr Arg Gly Asp Ser Thr Ser Ser Thr Arg Ser Ala 385390 395 400 Gly Lys Leu Ser Lys Thr Gly Ser Glu Ser Ser Ser Ser Ala GlySer 405 410 415 Ser Gly Ser Leu Ser Arg Thr His Pro Gln Ser Thr Ala LeuThr Ser 420 425 430 Ser Val Ala Ala Gly Ser Pro Gly Cys Met Ala Tyr SerGlu Asn Gly 435 440 445 Met Gly Gly Gln Val Pro Pro Ser Ser Thr Ser TyrIle Leu Leu Pro 450 455 460 Leu Glu Ser Ala Thr Gly Ile Pro Pro Gly SerIle Leu Leu Asn Pro 465 470 475 480 His Thr Gly Gln Pro Phe Val Asn ProAsp Gly Thr Pro Ala Ile Tyr 485 490 495 Asn Pro Pro Gly Ser Gln Gln ThrLeu Arg Gly Thr Val Gly Gly Gln 500 505 510 Pro Gln Gln Pro Pro Gln GlnGln Pro Ser Pro Gln Pro Gln Gln Gln 515 520 525 Val Gln Ala Ser Gln ProGln Met Ala Gly Pro Leu Val Thr Gln Arg 530 535 540 Glu Glu Leu Ala AlaGln Phe Ser Gln Leu Ser Met Ser Arg Gln Ser 545 550 555 560 Ser Gly AspThr Pro Glu Pro Pro Ser Gly Thr Val Tyr Pro Ala Ser 565 570 575 Leu LeuPro Gln Thr Ala Gln Pro Gln Ser Tyr Val Ile Thr Ser Ala 580 585 590 GlyGln Gln Leu Ser Thr Gly Gly Phe Ser Asp Ser Gly Pro Pro Ile 595 600 605Ser Gln Gln Val Leu Gln Ala Pro Pro Ser Pro Gln Gly Phe Val Gln 610 615620 Gln Pro Pro Pro Ala Gln Met Ser Val Tyr Tyr Tyr Pro Ser Gly Gln 625630 635 640 Tyr Pro Thr Ser Thr Ser Gln Gln Tyr Arg Pro Leu Ala Ser ValGln 645 650 655 Tyr Ser Ala Gln Arg Ser Gln Gln Ile Pro Gln Thr Thr GlnGln Ala 660 665 670 Gly Tyr Gln Pro Val Leu Ser Gly Gln Gln Gly Phe GlnGly Met Met 675 680 685 Gly Val Gln Gln Ser Ala His Ser Gln Gly Val MetSer Ser Gln Gln 690 695 700 Gly Ala Pro Val His Gly Val Met Val Ser TyrPro Thr Met Ser Ser 705 710 715 720 Tyr Gln Val Pro Met Thr Gln Gly SerGln Ala Val Pro Gln Gln Thr 725 730 735 Tyr Gln Pro Pro Ile Met Leu ProSer Gln Ala Gly Gln Gly Ser Leu 740 745 750 Pro Ala Thr Gly Met Pro ValTyr Cys Asn Val Thr Pro Pro Asn Pro 755 760 765 Gln Asn Asn Leu Arg LeuMet Gly Pro His Cys Pro Ser Ser Thr Val 770 775 780 Pro Val Met Ser AlaSer Cys Arg Thr Asn Cys Gly Asn Val Ser Asn 785 790 795 800 Ala Gly TrpGln Val Lys Phe 805 12 648 PRT Homo sapien 12 Met Ile Leu Leu Lys MetGlu Gln Glu Ile Ile Asp Phe Ile Ala Asp 1 5 10 15 Asn Asn Asn His TyrLys Lys Phe Pro Gln Met Ser Ser Tyr Gln Arg 20 25 30 Met Leu Val His ArgVal Ala Ala Tyr Phe Gly Leu Asp His Asn Val 35 40 45 Asp Gln Thr Gly LysSer Val Ile Ile Asn Lys Thr Ser Ser Thr Arg 50 55 60 Ile Pro Glu Gln ArgPhe Cys Glu His Leu Lys Asp Glu Lys Gly Glu 65 70 75 80 Glu Ser Gln LysArg Phe Ile Leu Lys Arg Asp Asn Ser Ser Ile Asp 85 90 95 Lys Glu Asp AsnGln Ser Val Cys Ser Gln Glu Ser Leu Phe Val Glu 100 105 110 Asn Arg LeuLeu Glu Asp Ser Asn Ile Cys Asn Glu Thr Tyr Lys Lys 115 120 125 Arg GlnLeu Phe Arg Gly Asn Arg Asp Gly Ser Gly Arg Thr Ser Gly 130 135 140 SerArg Gln Ser Ser Ser Glu Asn Glu Leu Lys Trp Ser Asp His Gln 145 150 155160 Arg Ala Trp Ser Ser Thr Asp Ser Asp Ser Ser Asn Arg Asn Leu Lys 165170 175 Pro Ala Met Thr Lys Thr Ala Ser Phe Gly Gly Ile Thr Val Leu Thr180 185 190 Arg Gly Asp Ser Thr Ser Ser Thr Arg Ser Thr Gly Lys Leu SerLys 195 200 205 Ala Gly Ser Glu Ser Ser Ser Ser Ala Gly Ser Ser Gly SerLeu Ser 210 215 220 Arg Thr His Pro Pro Leu Gln Ser Thr Pro Leu Val SerGly Val Ala 225 230 235 240 Ala Gly Ser Pro Gly Cys Val Pro Tyr Pro GluAsn Gly Ile Gly Gly 245 250 255 Gln Val Ala Pro Ser Ser Thr Ser Tyr IleLeu Leu Pro Leu Glu Ala 260 265 270 Ala Thr Gly Ile Pro Pro Gly Ser IleLeu Leu Asn Pro His Thr Gly 275 280 285 Gln Pro Phe Val Asn Pro Asp GlyThr Pro Ala Ile Tyr Asn Pro Pro 290 295 300 Thr Ser Gln Gln Pro Leu ArgSer Ala Met Val Gly Gln Ser Gln Gln 305 310 315 320 Gln Pro Pro Gln GlnGln Pro Ser Pro Gln Pro Gln Gln Gln Val Gln 325 330 335 Pro Pro Gln ProGln Met Ala Gly Pro Leu Val Thr Gln Ser Val Gln 340 345 350 Gly Leu GlnAla Ser Ser Gln Ser Val Gln Tyr Pro Ala Val Ser Phe 355 360 365 Pro ProGln His Leu Leu Pro Val Ser Pro Thr Gln His Phe Pro Met 370 375 380 ArgAsp Asp Val Ala Thr Gln Phe Gly Gln Met Thr Leu Ser Arg Gln 385 390 395400 Ser Ser Gly Glu Thr Pro Glu Pro Pro Ser Gly Pro Val Tyr Pro Ser 405410 415 Ser Leu Met Pro Gln Pro Ala Gln Gln Pro Ser Tyr Val Ile Ala Ser420 425 430 Thr Gly Gln Gln Leu Pro Thr Gly Gly Phe Ser Gly Ser Gly ProPro 435 440 445 Ile Ser Gln Gln Val Leu Gln Pro Pro Pro Ser Pro Gln GlyPhe Val 450 455 460 Gln Gln Pro Pro Pro Ala Gln Met Pro Val Tyr Tyr TyrPro Ser Gly 465 470 475 480 Gln Tyr Pro Thr Ser Thr Thr Gln Gln Tyr ArgPro Met Ala Pro Val 485 490 495 Gln Tyr Asn Ala Gln Arg Ser Gln Gln MetPro Gln Ala Ala Gln Gln 500 505 510 Ala Gly Tyr Gln Pro Val Leu Ser GlyGln Gln Gly Phe Gln Gly Leu 515 520 525 Ile Gly Val Gln Gln Pro Pro GlnSer Gln Asn Val Ile Asn Asn Gln 530 535 540 Gln Gly Thr Pro Val Gln SerVal Met Val Ser Tyr Pro Thr Met Ser 545 550 555 560 Ser Tyr Gln Val ProMet Thr Gln Gly Ser Gln Gly Leu Pro Gln Gln 565 570 575 Ser Tyr Gln GlnPro Ile Met Leu Pro Asn Gln Ala Gly Gln Gly Ser 580 585 590 Leu Pro AlaThr Gly Met Pro Val Tyr Cys Asn Val Thr Pro Pro Thr 595 600 605 Pro GlnAsn Asn Leu Arg Leu Ile Gly Pro His Cys Pro Ser Ser Thr 610 615 620 ValPro Val Met Ser Ala Ser Cys Arg Thr Asn Cys Ala Ser Met Ser 625 630 635640 Asn Ala Gly Trp Gln Val Lys Phe 645 13 651 PRT Homo sapien 13 ArgAsp Arg Met Ile Leu Leu Lys Met Glu Gln Glu Ile Ile Asp Phe 1 5 10 15Ile Ala Asp Asn Asn Asn His Tyr Lys Lys Phe Pro Gln Met Ser Ser 20 25 30Tyr Gln Arg Met Leu Val His Arg Val Ala Ala Tyr Phe Gly Leu Asp 35 40 45His Asn Val Asp Gln Thr Gly Lys Ser Val Ile Ile Asn Lys Thr Ser 50 55 60Ser Thr Arg Ile Pro Glu Gln Arg Phe Cys Glu His Leu Lys Asp Glu 65 70 7580 Lys Gly Glu Glu Ser Gln Lys Arg Phe Ile Leu Lys Arg Asp Asn Ser 85 9095 Ser Ile Asp Lys Glu Asp Asn Gln Ser Val Cys Ser Gln Glu Ser Leu 100105 110 Phe Val Glu Asn Arg Leu Leu Glu Asp Ser Asn Ile Cys Asn Glu Thr115 120 125 Tyr Lys Lys Arg Gln Leu Phe Arg Gly Asn Arg Asp Gly Ser GlyArg 130 135 140 Thr Ser Gly Ser Arg Gln Ser Ser Ser Glu Asn Glu Leu LysTrp Ser 145 150 155 160 Asp His Gln Arg Ala Trp Ser Ser Thr Asp Ser AspSer Ser Asn Arg 165 170 175 Asn Leu Lys Pro Ala Met Thr Lys Thr Ala SerPhe Gly Gly Ile Thr 180 185 190 Val Leu Thr Arg Gly Asp Ser Thr Ser SerThr Arg Ser Thr Gly Lys 195 200 205 Leu Ser Lys Ala Gly Ser Glu Ser SerSer Ser Ala Gly Ser Ser Gly 210 215 220 Ser Leu Ser Arg Thr His Pro ProLeu Gln Ser Thr Pro Leu Val Ser 225 230 235 240 Gly Val Ala Ala Gly SerPro Gly Cys Val Pro Tyr Pro Glu Asn Gly 245 250 255 Ile Gly Gly Gln ValAla Pro Ser Ser Thr Ser Tyr Ile Leu Leu Pro 260 265 270 Leu Glu Ala AlaThr Gly Ile Pro Pro Gly Ser Ile Leu Leu Asn Pro 275 280 285 His Thr GlyGln Pro Phe Val Asn Pro Asp Gly Thr Pro Ala Ile Tyr 290 295 300 Asn ProPro Thr Ser Gln Gln Pro Leu Arg Ser Ala Met Val Gly Gln 305 310 315 320Ser Gln Gln Gln Pro Pro Gln Gln Gln Pro Ser Pro Gln Pro Gln Gln 325 330335 Gln Val Gln Pro Pro Gln Pro Gln Met Ala Gly Pro Leu Val Thr Gln 340345 350 Ser Val Gln Gly Leu Gln Ala Ser Ser Gln Ser Val Gln Tyr Pro Ala355 360 365 Val Ser Phe Pro Pro Gln His Leu Leu Pro Val Ser Pro Thr GlnHis 370 375 380 Phe Pro Met Arg Asp Asp Val Ala Thr Gln Phe Gly Gln MetThr Leu 385 390 395 400 Ser Arg Gln Ser Ser Gly Glu Thr Pro Glu Pro ProSer Gly Pro Val 405 410 415 Tyr Pro Ser Ser Leu Met Pro Gln Pro Ala GlnGln Pro Ser Tyr Val 420 425 430 Ile Ala Ser Thr Gly Gln Gln Leu Pro ThrGly Gly Phe Ser Gly Ser 435 440 445 Gly Pro Pro Ile Ser Gln Gln Val LeuGln Pro Pro Pro Ser Pro Gln 450 455 460 Gly Phe Val Gln Gln Pro Pro ProAla Gln Met Pro Val Tyr Tyr Tyr 465 470 475 480 Pro Ser Gly Gln Tyr ProThr Ser Thr Thr Gln Gln Tyr Arg Pro Met 485 490 495 Ala Pro Val Gln TyrAsn Ala Gln Arg Ser Gln Gln Met Pro Gln Ala 500 505 510 Ala Gln Gln AlaGly Tyr Gln Pro Val Leu Ser Gly Gln Gln Gly Phe 515 520 525 Gln Gly LeuIle Gly Val Gln Gln Pro Pro Gln Ser Gln Asn Val Ile 530 535 540 Asn AsnGln Gln Gly Thr Pro Val Gln Ser Val Met Val Ser Tyr Pro 545 550 555 560Thr Met Ser Ser Tyr Gln Val Pro Met Thr Gln Gly Ser Gln Gly Leu 565 570575 Pro Gln Gln Ser Tyr Gln Gln Pro Ile Met Leu Pro Asn Gln Ala Gly 580585 590 Gln Gly Ser Leu Pro Ala Thr Gly Met Pro Val Tyr Cys Asn Val Thr595 600 605 Pro Pro Thr Pro Gln Asn Asn Leu Arg Leu Ile Gly Pro His CysPro 610 615 620 Ser Ser Thr Val Pro Val Met Ser Ala Ser Cys Arg Thr AsnCys Ala 625 630 635 640 Ser Met Ser Asn Ala Gly Trp Gln Val Lys Phe 645650 14 89 PRT Homo sapien 14 Met Ser Glu Gln Gly Asp Leu Asn Gln Ala IleAla Glu Glu Gly Gly 1 5 10 15 Thr Glu Gln Glu Thr Ala Thr Pro Glu AsnGly Ile Val Lys Ser Glu 20 25 30 Ser Leu Asp Glu Glu Glu Lys Leu Glu LeuGln Arg Arg Leu Glu Ala 35 40 45 Gln Asn Gln Glu Arg Arg Lys Ser Lys SerGly Ala Gly Lys Gly Lys 50 55 60 Leu Thr Arg Ser Leu Ala Val Cys Glu GluSer Ser Ala Arg Pro Gly 65 70 75 80 Gly Glu Ser Leu Gln Asp Gln Thr Leu85 15 88 PRT Mus musculus 15 Met Ser Glu Gln Gly Gly Leu Thr Pro Thr IleLeu Glu Glu Gly Gln 1 5 10 15 Thr Glu Pro Glu Ser Ala Pro Glu Asn GlyIle Leu Lys Ser Glu Ser 20 25 30 Leu Asp Glu Glu Glu Lys Leu Glu Leu GlnArg Arg Leu Ala Ala Gln 35 40 45 Asn Gln Glu Arg Arg Lys Ser Lys Ser GlyAla Gly Lys Gly Lys Leu 50 55 60 Thr Arg Ser Leu Ala Val Cys Glu Glu SerSer Ala Arg Ser Gly Gly 65 70 75 80 Glu Ser His Gln Asp Gln Thr Leu 85

1. An isolated polynucleotide which codes without interruption for ahuman TARPP polypeptide having an amino acid sequence set forth in SEQID NO 2 (Br137E), SEQ ID NO 4 (Br137A), SEQ ID NO 6 (Br137B), SEQ ID NO8 (Br137C), or a complement thereto.
 2. An isolated polynucleotide ofclaim 1, having the nucleotide sequence set forth in SEQ ID NO: 1, 3, 5,or
 7. 3. An isolated polynucleotide comprising, polynucleotide sequencehaving 99% or more sequence identity to the polynucleotide sequence setforth in SEQ ID NO 2 (Br137E), SEQ ID NO 4 (Br137A), SEQ ID NO 6(Br137B), or SEQ ID NO 8 (Br137C), which codes without interruption fora human TARPP, or a complement thereto, and which has nucleic acidbinding activity.
 4. An isolated polynucleotide of a human TARPP ofclaim 1 consisting essentially of, a polynucleotide sequence coding foramino acids 267-300, 312-331, 1-161, 88-161, effective specificfragments thereof, or complements thereto.
 5. An isolated polynucleotideof claim 4, wherein said fragment is effective in a polymerase chainreaction.
 6. An isolated polypeptide coding for human TARPP having anamino acid sequence set forth in SEQ ID NO 2 (Br137E), SEQ ID NO 4(Br137A), SEQ ID NO 6 (Br137B), and SEQ ID NO 8 (Br137C).
 7. An isolatedpolypeptide consisting essentially of a polypeptide coded for by apolynucleotide sequence of claim
 4. 8. An isolated polypeptidecomprising an amino acid sequence having 99% or more sequence identityto a human TARPP of claim 1 and having the amino acid sequence set forthin SEQ ID NO 2 (Br137E), SEQ ID NO 4 (Br137A), SEQ ID NO 6 (Br137B), orSEQ ID NO 8 (Br137C).
 9. A method of modulating T-cells, comprising,contacting T-cells with an agent which is effective for regulating ahuman TARPP gene of claim 1 expressed in said cells, or for modulatingthe biological activity of a polypeptide encoded thereby.
 10. A methodof claim 9, wherein said agent is an antibody or an antisensepolynucleotide effective to inhibit translation of said gene.
 11. Amethod treating a disease of the immune or nervous system, comprising,administering to a subject in need thereof an amount of an agenteffective for modulating the expression of a human TARPP of claim 1, orfor modulating the biological activity of a polypeptide encoded thereby.12. A method of detecting expression of a gene coding for human TARPP,comprising, contacting a sample comprising nucleic acid with apolynucleotide probe specific for a human TARPP of claim 1 underconditions effective for said probe to hybridize specifically with saidhuman TARPP, and detecting hybridization between said probe and saidhuman TARPP.
 13. A method of claim 12, wherein said detecting isperformed by: Northern blot analysis, polymerase chain reaction (PCR),reverse transcriptase PCR, RACE PCR, or in situ hybridization.
 14. Amethod of assessing a therapeutic or preventative intervention in asubject having a disease of the immune or nervous system, comprising,determining the expression levels of a human TARPP of claim 1 in asample comprising immune or neuronal cells.
 15. A method for identifyingan agent that modulates a human TARPP gene in cells expressing saidgene, comprising, contacting cells expressing human TARPP of claim 1with a test agent under conditions effective for said test agent tomodulate the expression of a gene coding for said human TARPP, anddetermining whether said test agent modulates said human TARPP.
 16. Amethod of claim 15, wherein said agent is an antisense polynucleotide toa target polynucleotide sequence selected from SEQ ID NO. 1 (Br137E), 3(Br137A), 5 (Br137B), or 7 (Br137C), and which is effective to inhibittranslation of said human TARPP.
 17. A method for identifying an agentthat modulates the biological activity of a human TARPP polypeptide incells expressing said polypeptide, comprising, contacting cellsexpressing a human TARPP polynucleotide of claim 1 with a test agentunder conditions effective for said test agent to modulate thebiological activity of a human TARPP polypeptide coded for by saidpolynucleotide, and determining whether said test agent modulates saidhuman TARPP.
 18. A method of claim 17, wherein said agent is apolynucleotide which binds to said polypeptide.
 19. A method ofdetecting polymorphisms in human TARPP comprising, comparing thestructure of: genomic DNA comprising all or part of human TARPP, mRNAcomprising all or part of human TARPP, cDNA comprising all or part ofhuman TARPP, or a polypeptide comprising all or part of human TARPP,with the structure of human TARPP of claim
 1. 20. A method of claim 19,wherein said polymorphism is a nucleotide deletion, substitution,inversion, or transposition.
 21. A human cell whose genome comprises afunctional disruption of human TARPP in the region comprising the codingsequence for amino acids 1-161 of a human TARPP of claim
 1. 22. A humancell whose genome comprises a deletion of a coding sequence for aminoacids 267-300 and/or 312-331 of a human TARPP of claim
 1. 23. A methodof advertising human TARPP for sale, commercial use, or licensing,comprising, displaying in a computer-readable medium a polynucleotide oramino acid sequence for a human TARPP of claim 1, effective specificfragments thereof, or complements thereto.
 24. An antibody which isspecific-for a human TARPP, said antibody which is specific for anepitope present in amino acid sequences 1-161, 88-161, 267-300, 312-331,or a polypeptide comprising amino acid 312, of a human TARPP of claim 1.